The epidemiology of osteoporosis in Italian postmenopausal women according to the National Bone Health Alliance (NBHA) diagnostic criteria: a multicenter cohort study.

PURPOSE: The study was aimed at evaluating the prevalence of osteoporosis, defined by BMD and the National Bone Health Alliance (NBHA) criteria, and the prevalence of clinical risk factors for fractures in Italian postmenopausal women. METHODS: This is a cross-sectional, multicenter, cohort study evaluating 3247 postmenopausal women aged ≥ 50 and older in different areas of Italy in the period 2012-2014. All the participants were evaluated as far as anthropometrics; questionnaires for FRAX® and DeFRA calculation were administered and bone mineral density was measured at lumbar spine, femoral neck and total hip by DXA. RESULTS: The prevalence of osteoporosis, as assessed by BMD and NBHA criteria was 36.6 and 57%, respectively. Mean ± SD values of FRAX® and DeFRA were: 10.2 ± 7.3 and 11 ± 9.4 for major fractures, and 3.3 ± 4.9 and 3.9 ± 5.9 for hip fractures, respectively. Among clinical risk factors for fracture, the presence of previous fracture, particularly non-spine/non-hip fracture, parental history of hip fracture and current smoking were the most commonly observed. CONCLUSIONS: Our study showed that more that the half of postmenopausal women aged 50 and older in Italy has osteoporosis on the basis of the NBHA criteria. There is a relevant high risk of femur fracture, as assessed by the FRAX® and DeFRA and previous fracture, parental history of hip fracture and current smoking are the most common risk factors. The data should be considered particularly in relation to the need to increase prevention strategies on modifiable risk factors and therapeutic intervention.

Guidelines for the diagnosis, prevention and management of osteoporosis.

Osteoporosis poses a significant public health issue. National Societies have developed Guidelines for the diagnosis and treatment of this disorder with an effort of adapting specific tools for risk assessment on the peculiar characteristics of a given population. The Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS) has recently revised the previously published Guidelines on the diagnosis, riskassessment, prevention and management of primary and secondary osteoporosis. The guidelines were first drafted by a working group and then approved by the board of SIOMMMS. Subsequently they received also the endorsement of other major Scientific Societies that deal with bone metabolic disease. These recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on leading experts' experience and opinion, and on good clinical practice. The osteoporosis prevention should be based on the elimination of specific risk factors. The use of drugs registered for the treatment of osteoporosis are recommended when the benefits overcome the risk, and this is the case only when the risk of fracture is rather high as measured with variables susceptible to pharmacological effect. DeFRA (FRAX® derived fracture risk assessment) is recognized as a useful tool for easily estimate the long-term fracture risk. Several secondary forms of osteoporosis require a specific diagnostic and therapeutic management.

Longitudinal changes of trabecular bone score after estrogen deprivation: effect of menopause and aromatase inhibition.

PURPOSE: To examine the effects of the menopausal transition and treatment with aromatase inhibitors (AI) on trabecular bone score (TBS, a newly proposed index of bone architecture derived from DXA vertebral scans) and vertebral bone mineral density (BMD). METHODS: Retrospective cohort study on 29 women who became postmenopausal during a mean follow-up of 2.9 years (MP group) and 34 women treated with AI during a mean follow-up of 2.1 years (AI group). BMD was measured by DXA and TBS with a specific software. RESULTS: TBS decreased after menopause, but the change was significantly lower than that of the lumbar BMD (-4.6 vs. -6.8 %; mean difference: 2.2 %; p = 0.016). An even larger difference was observed in the AI group (-2.1 vs. -5.9 %; mean difference: 3.8 %; p = 0.002). CONCLUSIONS: The decrease of TBS induced by menopause or treatment with AI is significantly lower than that of lumbar BMD.

Uses and misuses of statistics: the case of strontium ranelate and the number needed to treat.

In the last 15 years, several pharmacological agents for the prevention of fractures have been developed and commercialized. Most of them showed to be effective in reducing fracture risk. The enhanced availability of drugs to prevent fractures has generated a fierce competition among pharmaceutical companies to conquer a share of the potential market, often with claims of superiority of a drug over another without direct comparisons. The definitive way to compare different treatments would require randomized head to head trials. These trials are expensive, need large samples and are unlikely to be ever performed. Therefore, it has become a common practice to compare pharmacological agents through observational studies on administrative databases or by the indirect comparison of the results of individual randomised-controlled trials (RCT) and their meta-analyses. These studies may produce evidence of clinical value, complementary to that given by RCT. However, without a proper and complete analysis, they may result in a biased picture of effectiveness and be completely misleading. In this article, we critically disclose how such competition may produce biased and misleading picture of evidence, by reviewing the significance of the number needed to treat, absolute risk reduction and relative risk reduction in relation to vertebral fractures prevention with available drugs.

Assessment of the 10-year risk of fracture in Italian postmenopausal women using FRAX®: a north Italian multicenter study.

The aim of the study was to estimate the absolute risk of fracture in a sample of postmenopausal women with the Italian version of FRAX®, using femoral neck bone mineral density (BMD) and 3 internationally validated clinical risk factors (CRFs) (history of fragility fracture, family history of hip fracture, current smoking). We retrospectively studied 9586 women (mean age 64.1 yr) examined in three osteoporosis centers from Northern Italy over two years (2001-2002). The risk of major osteoporotic (clinical spine, hip, forearm and humerus) and hip fractures was estimated using the online version of the FRAX algorithm adapted for Italy. The median 10-year risk was 7.5% for osteoporotic fracture and 1.7% for hip fracture. 25% of subjects had a 10-year risk ≥ 12.1% for osteoporotic fracture and ≥ 4.1% for hip fracture. The median 10-year risk of fracture increased with the number of prevalent CRFs. For major osteoporotic fractures risk rose from 6.3% to 10.9%, 21.4% and 40.9% with 1, 2 and 3 prevalent CRFs, respectively. For hip fractures the corresponding figures were: 1.3%, 2.7%, 7.0% and 21.9%, respectively. However, it must be emphasized that in 2 out of 3 women, none of the CRFs examined was present and the assessment of risk was limited to age and BMD. Our data provide the first description of the effect of the combination of BMD, age and CRFs on fracture risk stratification in a large sample of Italian postmenopausal women using FRAX®. The results are a useful starting point to define criteria for the application of FRAX® in clinical practice in Italy.

Validation and further development of the WHO 10-year fracture risk assessment tool in Italian postmenopausal women: project rationale and description.

The threshold for pharmacological intervention for osteoporosis remains controversial. Tools predicting the future risk of new fractures are increasingly used to establish a convenient individual risk/benefit ratio for a long term treatment. FRAX® is likely to become the most widely used tool for assessing fracture risk also for the WHO endorsement. The inevitable limitations will not hamper its value. As for any tool like this a continuous process of validation and further development is highly warranted. The predictive and clinical value of FRAX® has to be tested in individual countries by exploring also the inclusion of additional specific relatively uncommon risk factors. The DeFRA project is intended to validate in a large cohort of postmenopausal women a new algorithm derived from FRAX®. Both, the coefficients of continuous variable and the gradients for clinical risk factors should not be considered as conclusive for the routine clinical use. The new tool will be offered for the routine clinical use only at the completion of the DeFRA project, requiring the prospective collection of at least 60.000 patient-years. Here we report the rational and the design of the project.

Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients.

Osteopontin (OPN) is a multifunctional bone matrix glycoprotein that is involved in angiogenesis, cell survival and tumor progression. In this study we show that human myeloma cells directly produce OPN and express its major regulating gene Runx2/Cbfa1. The activity of Runx2/Cbfa1 protein in human myeloma cells has also been demonstrated. Moreover, using small interfering RNA (siRNA) to silent Runx2 in myeloma cells, we suppressed OPN mRNA and protein expression. OPN production in myeloma cells was stimulated by growth factors as IL-6 and IFG-1 and in turn OPN stimulated myeloma cell proliferation. In an 'in vitro' angiogenesis system we showed that OPN production by myeloma cells is critical for the proangiogenic effect of myeloma cells. The expression of OPN by purified bone marrow (BM) CD138(+) cells has also been investigated in 60 newly diagnosed multiple myeloma (MM) patients, finding that 40% of MM patients tested expressed OPN. Higher OPN levels have been detected in the BM plasma of MM patients positive for OPN as compared to controls. Moreover, significantly higher BM angiogenesis has been observed in MM patients positive for OPN as compared to those negative. Our data highlight that human myeloma cells with active Runx2/Cbfa1 protein directly produce OPN that is involved in the pathophysiology of MM-induced angiogenesis.

Osteolytic lesions, cytogenetic features and bone marrow levels of cytokines and chemokines in multiple myeloma patients: Role of chemokine (C-C motif) ligand 20.

The relationship between bone marrow (BM) cytokine and chemokine levels, cytogenetic profiles and skeletal involvement in multiple myeloma (MM) patients is not yet defined. This study investigated a cohort of 455 patients including monoclonal gammopathy of uncertain significance (MGUS), smoldering MM and symptomatic MM patients. Skeletal surveys, positron emission tomography (PET)/computerized tomography (CT) and magnetic resonance imaging (MRI) were used to identify myeloma bone disease. Significantly higher median BM levels of both C-C motif Ligand (CCL)3 and CCL20 were found in MM patients with radiographic evidence of osteolytic lesions as compared with those without, and in all MM patients with positive PET/CT scans. BM levels of CCL3, CCL20, Activin-A and Dickkopf-1 (DKK-1) were significantly higher in patients with high bone disease as compared with patients with low bone disease. Moreover, CCL20 BM levels were significant predictors of osteolysis on X-rays by multivariate logistic analysis. On the other hand, DKK-1 levels were related to the presence of MRI lesions independently of the osteolysis at the X-rays. Our data define the relationship between bone disease and the BM cytokine and chemokine patterns highlighting the tight relationship between CCL20 BM levels and osteolysis in MM.

Humeral fractures due to low-energy trauma: an epidemiological survey in patients referred to a large emergency department in Northern Italy.

UNLABELLED: This survey describes the epidemiology of approximately 1800 low-energy humeral fractures seen in a large emergency department in Northern Italy over 7 years (2007-2013), highlighting the differences from previous Italian studies. PURPOSE: The purpose of this study was to determine the incidence of humeral fractures due to low-energy trauma in patients 40 years of age or older referred to a large Emergency Department (Parma, Northern Italy) in a 7-year period (2007-2013). METHODS: All humeral fractures referred to the emergency department of the Academic Hospital of Parma (the main hospital in the province with a catchment area of approximately 345,000) were retrieved from the hospital database using both ICD-9CM codes and text strings. The diagnosis of humeral fracture due to low-energy trauma was confirmed by medical records and X-ray reports, after exclusion of injuries due to a clear-cut high-energy trauma or cancer. RESULTS: The query identified 1843 humeral fractures (1809 first fractures), with a clear predominance in women (78 %). Fractures of the proximal humerus represented the large majority of humeral fractures (more than 85 %), with an incidence progressively increasing with age (more than 60-fold in women and 20-fold in men). Simultaneous fractures (hip in particular) were frequent especially after 85 years of age (1 out of 8 cases). When compared to other Italian studies, the incidence of humeral fractures was significantly lower than that derived from discharge data corrected for hospitalization rate (standardized rate ratio 0.74; p < 0.001), while the pattern of age-related changes was significantly different from that computed by applying the ratio between hip and humeral fractures observed in Malmö, Sweden, to the Italian hip fracture rates. CONCLUSIONS: This study gives an up-to-date description of the epidemiology of low-energy humeral fractures in Italy. Our results partly differ from previous Italian studies based on indirect estimations.

Increased serum concentrations of interleukin-6 (IL-6) and soluble IL-6 receptor in patients with Graves' disease.

Increased serum interleukin-6 (IL-6) concentrations have been reported in patients with thyroid destructive processes. In the present study we measured IL-6 and soluble IL-6 receptor (sIL-6R) concentrations in the serum of normal subjects and patients with Graves' disease using a high sensitivity sandwich enzyme-linked immunoassay. We found increased serum IL-6 and sIL-6R concentrations (69.3 fmol/L, and 964 pmol/L, respectively) in 49 hyperthyroid patients with Graves' disease (GD) compared to those in controls [55.8 fmol/L (P = 0.019) and 772 pmol/L (P = 0.007), respectively]. In 31 newly diagnosed GD patients, serum concentrations of IL-6 and sIL-6R during the hyperthyroid phase were elevated, and after therapy with methimazole only, serum sIL-6R concentrations returned to normal (940 vs. 726 pmol/L; P < 0.001) but serum IL-6 did not. Serum sIL-6R concentrations (mean +/- 2 SD) were higher in GD patients with active inflammatory thyroid-associated ophthalmopathy than those in patients with inactive or absent thyroid-associated ophthalmopathy (P < 0.05). In conclusion, we have demonstrated activation of the IL-6 system in GD and, for the first time, have measured and found increased serum sIL-6R concentrations in hyperthyroid GD patients.

Seasonal variation in the incidence of hip fractures in Emilia-Romagna and Parma.

Though some reports suggest the existence of seasonal changes in hip fracture incidence, with a peak in winter months, other investigations have failed to confirm this finding. In this study we present data on the month-to-month variability of hip fractures in Emilia-Romagna, a region of Northern Italy with a population of approximately four million inhabitants, and in Parma, a province of Emilia-Romagna (population of approximately 400,000). Data on cervical and trochanteric fractures were obtained from two sources: a) records of all operative procedures in the five orthopaedic centres serving the area of the Parma province; and b) a computerised database of all hospital discharges from public and private hospitals of Emilia-Romagna. In both cases, the analysis gave similar results, with no evidence of a consistent seasonal pattern in hip fracture rates.

Bisphosphonates stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis in young and aged mice in vivo.

Recent in vitro findings suggest that bisphosphonates, potent inhibitors of osteoclastic bone resorption, may also have a direct action on osteoblasts. The purpose of this study was to search for potential effects of etidronate and alendronate on the formation of early and late osteoblastic cell precursors by measuring the number of colony-forming units for fibroblasts (CFU-F) and colony-forming units for osteoblasts (CFU-OB) in murine and human bone marrow cultures. In murine marrow cultures, etidronate (10(-5) to 10(-9) mol/L) significantly stimulated the formation of CFU-F with a maximal effect at 10(-5) mol/L (mean increase over control values+/-SD: 106+/-17%;p < 0.001), whereas alendronate had a biphasic effect, being stimulatory at concentrations below 10(-7) mol/L (78+/-5%; p < 0.001), and inhibitory at higher doses. The formation of CFU-OB was also inhibited by both bisphosphonates at the highest concentrations (10(-5) mol/L and 10(-6) mol/L), but it was significantly stimulated at lower concentrations (from 10(-7) to 10(-9) mol/L for etidronate and 10(-7) to 10(-10) mol/I, for alendronate; p < 0.001). In human bone marrow cultures, alendronate (10(-8) to 10-(12) mol/L) increased CFU-F formation with a maximal effect at 10(-10) mol/L (161+/-12 %; p < 0.01). CFU-OB formation, observed only in the presence of dexamethasone (10(-8) mol/L), was markedly stimulated by alendronate at the above concentrations with a maximal increase at 10(-10) mol/L (133+/-34%; p < 0.001). The in vivo short-term effects of bisphosphonates on the formation of early osteoblast precursors were also studied in bone marrow cultures from young female mice treated with weekly subcutaneous injections of etidronate (0.3, 3, and 30 mg/kg) or alendronate (0.3, 3, and 30 microg/kg) and from aging female mice treated with the two lowest doses of both drugs. After 1 month of treatment, etidronate (0.3 and 3 mg/kg) and alendronate (0.3 and 3 microg/kg) significantly increased the number of CFU-F colonies in the bone marrow from young and old animals, whereas the highest dose of both drugs had no effect in young mice. Our results, together with previously reported observations of bone-forming effects in osteoporosis, suggest that bisphosphonates may have, in vivo, a potentially relevant influence on cells of the osteoblastic lineage, distinct from their inhibitory action on osteoclasts.

The comparative effect of ovarian hormone administration on bone mineral status in oophorectomized rats.

The effect of oophorectomy and hormone replacement therapy on cortical and trabecular bone mass was assessed in Sprague-Dawley rats. Bone mineral density (BMD) of the femur and the lumbar spine was determined by dual photon absorptiometry 4 months after surgery. Femoral mineral content was also determined. A significant decrease in bone density and in calcium content was observed after surgical castration. Bone mineral loss was prevented by either progesterone or estrogen, while the combination of progesterone and estrogen had no effect on the bone mineral content. The present study suggests the possibility that estrogen-progestin treatment may be less effective than a therapy with estrogen alone, and that further study on the effect of progesterone alone would be worthwhile.

Serum interleukin-6, soluble interleukin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-related changes.

Growing evidence suggests that interleukin-6 (IL-6) may play a pathogenetic role in postmenopausal bone loss and in other age-related pathological conditions. In this study, we have examined the age-related changes in the serum levels of IL-6 and the soluble receptors that modulate its biological activity--soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130)--in 220 women (from 25 to 104yr old), including 22 centenarians. Serum IL-6 rose exponentially with age (r=0.74, p<0.0001). The median level of IL-6 increased almost ten-fold with age, from 1.16pg/ml in premenopausal women to 10.27pg/ml in centenarians. Serum sIL-6R and sgp130 showed an increase until the seventh decade and a progressive decrease in older ages (r=0.39, p<0.0001 and r=0.26, p=0.008, respectively). IL-6, sIL-6R and sgp130 were significantly higher in women within 10yr of menopause as compared to premenopausal subjects (1.51 vs. 1.16pg/ml, p=0.012; 41.9 vs. 35.7ng/ml, p=0.002; and 253.4 vs. 230.7ng/ml, p=0.008, respectively). In postmenopausal women, a negative correlation was found between sIL-6R and the lumbar bone mineral density (BMD) (r=-0.28, p=0.002) even after adjusting for age and weight. Furthermore, sIL-6R levels were higher in osteoporotic compared to normal women (47.9 vs. 39.5ng/ml, p=0.001). In conclusion, our results show that the serum levels of IL-6, sIL-6R and sgp130 exhibit different patterns of age- and menopause-related changes, and that the biological activity of IL-6 may be increased with age with potential implications in the age-related diseases such as osteoporosis.

Serum concentrations of proinflammatory cytokines in Graves' disease: effect of treatment, thyroid function, ophthalmopathy and cigarette smoking.

OBJECTIVE: In the present study we have measured the concentrations of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1Ra) in the serum of patients with Graves' disease (GD). By multivariate analysis, we have evaluated the effect of antithyroid treatment, thyroid function, the presence or absence of active thyroid-associated ophthalmopathy (TAO), the patient's smoking habits and the relation to circulating anti-thyrotropin (TSH) receptor (TRAb) and anti-thyroperoxidase antibodies (TPOAb). SUBJECTS: We studied 84 GD patients, 51 untreated and 33 receiving methimazole (MMI) therapy. Twenty-three (45%) untreated patients and 18 (54%) patients on MMI had active TAO. We also studied 67 normal subjects as controls. Thirty-one GD patients (43%) and 16 controls (36%) were smokers. RESULTS: Serum IL-6 concentrations were significantly higher in both untreated patients (P<0.001) and treated patients (P<0.006), when compared with controls. Serum sIL-6R concentrations were significantly affected by treatment (P=0.001). Serum IL-1Ra concentrations were not different in GD patients, whether treated or untreated, compared with controls. Serum IL-6 concentrations were not influenced by thyroid function and there was a significant interaction between treatment and the presence of active TAO (P=0.003). In hyperthyroid patients with active TAO serum, sIL-6R concentrations were significantly higher than in those with inactive TAO (P=0.003). In untreated GD patients there was no significant effect of thyroid function and TAO activity on the serum concentrations of TNF-alpha and IL-1 beta. Serum IL-1Ra concentrations were not affected by the presence of TAO. Smoking had no effect on serum IL-6, sIL-6R, TNF-alpha, IL-1 beta and IL-1Ra concentrations, even in the presence of an active TAO. Serum concentrations of IL-6, sIL-6R, TNF-alpha and IL-1 beta and IL-1Ra were not different in patients with and without TRAb or TPOAb, in relation to either thyroid function, TAO activity or smoking. CONCLUSIONS: Our work shows that: (i) the proinflammatory cytokine pattern in GD is greatly influenced by antithyroid drug treatment; (ii) the increased circulating IL-6/sIL-6R concentrations observed in patients with active TAO may derive from the activation of humoral reactions in sites other than the thyroid; and, (iii) cigarette smoking has no effect on serum IL-1/IL-1Ra concentrations in TAO.

Impaired PRL response to hyperthermia in alcoholic men.

The aim of this study was to evaluate the release of PRL to sauna-induced hyperthermia in 10 chronically alcohol-addicted male subjects after a few weeks of abstinence. In contrast with normal men the alcoholic men showed higher basal levels of PRL and the exposure to hyperthermic stress did not stimulate in PRL secretion. These results indicate that chronic alcohol abuse is associated with functional pituitary alterations similar to other states of addiction.

Metyrapone effects on beta-endorphin, ACTH and cortisol levels after chronic opiate receptor stimulation in man.

The aim of this study was to evaluate beta-endorphin, ACTH, and cortisol plasma levels during metyrapone administration in man after chronic opioid receptor stimulation. Metyrapone (750 mg every 4 hr for 6 doses) was administered to ten male heroin addicts, who had been on a maintenance therapy with methadone for at least 6 months and to ten healthy sex- and age-matched volunteers. Before metyrapone administration the basal levels of cortisol and ACTH were significantly decreased in addicts as compared to normal controls, while plasma beta-endorphin was not different. The response of beta-endorphin and ACTH to metyrapone administration was significantly blunted in addicts (p less than 0.01). These results suggest that the chronic stimulation of opiate receptors can impair the function of the anterior pituitary gland.

Chronic effects of marihuana smoking on luteinizing hormone, follicle-stimulating hormone and prolactin levels in human males.

The purpose of this investigation was to assess the chronic effects of marihuana smoking on the basal and stimulated secretion of the pituitary hormones luteinizing hormone (LH), follicle-stimulating (FSH) and prolactin (PRL). Ten male chronic marihuana users and 10 age- and sex-matched healthy volunteers were studied by measuring hormone levels before and after i.v. administration of thyrotropin releasing hormone (TRH) and gonadotropin releasing hormone (GnRH). The basal and stimulated levels of LH were reduced in marihuana users, whereas FSH and PRL levels and responses were not different from the control subjects. The chronic use of marihuana may selectively impair the hypothalamic control mechanisms regulating LH secretion.

Salmon calcitonin given by nasal spray or by injection does not increase beta-endorphin levels in normal men.

It has been suggested that the analgesic action of calcitonin (CT) might involve a stimulation of beta-endorphin (beta-EP) release. To verify whether salmon CT modifies the circulating levels of beta-EP, and whether the route of administration plays any role in this response, we have studied 10 healthy male volunteers, aged 30-40 yr. Each of them was studied on 4 different days, after administration of placebo or salmon CT (100 UI) by the intravenous, intramuscular and nasal route, in random order. Ionized calcium tended to decrease, especially after intravenous CT, but there was no change in plasma beta-EP levels, regardless of the route of administration. It is therefore unlikely that circulating beta-EP mediates any biological effect of CT.

Impaired calcitonin secretion following stimulation in spasmophilic women.

Calcitonin (CT) secretion following stimulation was studied in 9 young women suffering from spasmophilia, this having been diagnosed by clinical and electromyographic criteria. The controls were 9 women, matched by age, who responded negatively to the diagnostic tests. After rapid intravenous infusion (60 sec) of 4 mg/kg/lean body mass of calcium (as gluconate), CT concentration increased measurably (p less than 0.0001) in the controls, while remaining unchanged in the spasmophilic. The average increase per cent vs. the baseline values was 225% in the controls and 34% in those with spasmophilia (p less than 0.005). 5 out of 9 of the patients showed a completely flat curve. This finding, due to a diminished CT reserve in spasmophilia, may be considered a possible diagnostic feature as well as a fundamental pathological element in the reduction of the intracellular calcium pool responsible for the neuromuscular hyperexcitability. Moreover, the therapeutic use of the hormone in this condition is to be encouraged.