Monurelle Biogel® vaginal gel in the treatment of vaginal dryness in postmenopausal women.

OBJECTIVES: To evaluate efficacy, tolerability and safety of Monurelle Biogel® vaginal gel for treatment of vaginal dryness. METHODS: Multicenter, national, randomized, controlled vs. no-treatment, open-label study. Ninety-five postmenopausal women were randomized (48 to Monurelle Biogel® and 47 to no treatment). Primary endpoint was the change of Verbal Rating Scale (VRS) total score of vaginal atrophy (VA) symptoms after 8-week treatment. The main secondary endpoints were VRS single-item score, Vaginal Health Index (VHI) score, Maturation Index (MI), Female Sexual Function Index (FSFI), and Female Sexual Distress Scale-Revised (FSDS-R). RESULTS: The VRS total score was statistically significant in favor of the treatment group on day 28 (p = 0.001) but not on day 56 (p = 0.064). By excluding women who were not sexually active, the total VRS scores reached the criteria for clinical success in 27/43 subjects (62.8%) in the control arm and in 38/46 subjects (82.6%) in the treatment arm (p = 0.035) on day 56. The VHI score significantly changed in the active arm (4.71 ± 4.85 vs. 0.28 ± 1.71) (p < 0.001) on day 56. Even the MI significantly improved, with an increase in the percentage of superficial cells (p = 0.01). The improvements in both VHI and MI were still present at the follow-up visit after the discontinuation of the treatment (day 84). Sexual function and distress showed a statistical significant difference on day 56. CONCLUSIONS: Monurelle Biogel® vaginal gel applied twice daily for 8 weeks is effective in relieving vaginal dryness and other VA symptoms. Such a clinical meaningful effect persists at least 4 weeks and is supported by an improvement in the vaginal environment. Trial Registration clinicaltrials.gov Identifier: NCT02994342.

Correlates of sexual functioning in Italian menopausal women.

OBJECTIVES: To analyze the sexuality of Italian menopausal women. DESIGN: Cross-sectional study. POPULATION: Menopausal women consecutively observed during the study period in menopause clinics. METHODS: Women were interviewed about their current and premenopausal sexual activity: sexual intercourse frequency and self-rated sexual desire, capacity for orgasm and sexual satisfaction were recorded. Women were defined as having poor sexual functioning if they had one or less sexual intercourses per week or answered 'absent/poor' to the questions about the sexual domains. RESULTS: Oral hormone therapy (HT) use (odds ratio (OR) 0.43 for desire, 0.54 for orgasm and 0.56 for overall sexual satisfaction, all p < 0.001) and transdermal HT (OR 0.38, 0.53 and 0.53, respectively, all p < 0.001) were significantly associated with lower risk of poor sexual functioning. Higher physical and mental component scores (PCS and MCS, range 0-100) of the Short Form-12 are inversely related to poor sexual functioning (OR by point 0.96, 0.95, 0.95 for PCS and 0.96, 0.96 and 0.95, for MCS, respectively, all p < 0.001). Pain during and symptoms after sexual intercourse were significantly related to desire (OR 1.96 and 1.78, respectively), orgasm (OR 2.22 and 2.06, respectively) and sexual satisfaction (OR 2.02 and 1.79, respectively). The partner's health problems were associated with low sexual intercourse frequency (OR 4.18, p < 0.001) and absent/poor overall satisfaction (OR 2.61, p < 0.001). CONCLUSIONS: This study shows that, in menopausal Italian women attending menopause clinics, sexual function is associated with the quality of sexual life in reproductive age, partner's health status, current quality of life, HT and occurrence of pain during and symptoms after sexual intercourse.

Natriuretic hormone receptors and actions on bone endothelial cells.

[125I]Atrial natriuretic peptide (ANP) was used to identify ANP receptors on a clonal line of bovine bone endothelial (BBE) cells. Specific binding of [125I]ANP was saturable and of high affinity. Computer analysis of the equilibrium binding data indicated that the Scatchard plots are best fit by a straight line (Kd = 69.3 +/- 20.9 pM; binding capacity = 37.9 fmol/10(6) cells). The order of potency for competing with [125I]ANP binding was human ANP (hANP) > rat atriopeptin-1 (rAP-1) > porcine brain natriuretic peptide (pBNP) > porcine C-type natriuretic peptide. Affinity cross-linking studies indicated the presence of two major 130- and 70-kilodalton bands that specifically bound to hANP, rAP-1, pBNP, and porcine C-type natriuretic peptide. The binding of natriuretic peptides to BBE cells resulted in an increase in cGMP production and a significant decrease in Na+/K+/Cl- cotransport, without effects on cAMP intracellular accumulation. hANP, rAP-1, and pBNP at 100-nM concentrations, significantly inhibited PTH-induced cAMP production. Treatment with natriuretic hormones was also associated with an increase in 6-keto-prostaglandin F1 alpha levels in the culture medium of BBE cells and a higher cell growth rate. These studies demonstrate that bone endothelial cells bear receptors for natriuretic hormones associated with changes in PTH-induced cAMP production, prostaglandin production, and cell proliferation.

Urinary endothelin-1 excretion is enhanced by low-dose infusion of brain natriuretic peptide in normal humans.

To evaluate the functional relationship between cardiac natriuretic peptides and endothelin-1 within the human kidney, we studied the effects exerted by infusion of brain natriuretic peptide on urinary endothelin-1 excretion. We studied twice in a single-blind manner five normal volunteers who received a constant infusion of 5% dextrose (250 mL/h) or human brain natriuretic peptide-32 at a dose of 4 pmol/kg per minute. Blood samples were drawn at intervals for measurement of hematocrit and concentrations of creatinine, electrolytes, brain natriuretic peptide, and endothelin-1. Urine was collected an intervals for measurement of flow rate and concentrations of creatinine, sodium, cGMP, and endothelin-1. Blood pressure and heart rate were measured every 15 minutes. Placebo administration did not change blood pressure, heart rate, or any of the other parameters measured in plasma and urine. As expected, brain natriuretic peptide infusion caused significant increases in its own plasma levels (basal versus peak levels [mean +/- SD], 1.45 +/- 0.20 versus 50.5 +/- 6.0 pmol/L, P < .01), in urinary cGMP (0.75 +/- 0.16 versus 1.92 +/- 0.81 fmol/min, P < .05), and in urinary sodium excretion (140.0 +/- 38.7 versus 624.2 +/- 181.6 mumol/min, P < .01). In addition, it caused an increase in urinary endothelin-1 excretion (4.32 +/- 2.11 versus 19.67 +/- 9.52 fmol/min, P < .05), without modifying plasma endothelin-1, blood pressure, heart rate, creatinine clearance, and urinary flow rate. Our data indicate that brain natriuretic peptide, at plasma levels comparable to those observed in patients with heart failure, causes a significant increase in urinary but not plasma endothelin-1, thus demonstrating a functional link between cardiac natriuretic peptides and renal release of endothelin-1.

Vitamin D and estrogen receptor allelic variants in Italian postmenopausal women: evidence of multiple gene contribution to bone mineral density.

Bone mass and bone turnover are under genetic control. Restriction fragment length polymorphisms (RFLPs) at the vitamin D receptor (VDR) gene locus have been recently correlated to bone mineral density (BMD) and rate of bone loss. However, agreement on this relationship is not universal. The existence of ethnical and environmental differences between populations, a health-based selection bias in several previous studies, and the involvement of other genes could explain these discordant findings. In this study, we examined the relationship of VDR and estrogen receptor (ER) gene RFLPs with lumbar spine and upper femur BMD in 426 Italian postmenopausal women, 57.7 +/- 0.4 yr old (144 normal, 106 osteopenic, and 176 osteoporotic). VDR gene RFLPs for ApaI, Bsm I, and TaqI restriction endonucleases and ER RFLPs for PvuII and XbaI restriction endonucleases were assessed by Southern blotting analysis and were indicated, respectively, as A-a, B-b, T-t, P-p, and X-x (uppercase letters signifying the absence and lowercase letters the presence of the restriction site). After correcting for potential confounding factors (age, height, weight, age since menopause, osteophytosis, and facet joint osteoarthritis), a statistically significant VDR genotype effect on lumbar BMD (P = 0.01, analysis of covariance), but not on femoral BMD, was detected, with subjects in AABBtt genotype showing a 13% lower BMD than those with aabbTT genotype (P < 0.05, Tukey's test). Moreover, a statistically significant prevalence of AABBtt genotype in osteoporotics, and of AabbTT and aabbTT genotypes in nonosteoporotics, were detected. Conversely, there was no significant relationship of ER genotype to either lumbar or femoral BMD, even though a trend for higher BMD values in women with the ER PP genotype (with respect to those with ER pp genotype) was detected. When mean lumbar BMD was calculated for women grouped by ER and VDR genotype, we observed a significant difference between those within the 2 opposite associations AABBtt-PPXX and aabbTT-ppxx (0.71 +/- 0.05 vs. 0.97 +/- 0.03 g/cm2, P < 0.05 Tukey's test). These results are consistent with a segregation of the VDR AABBtt genotype with a higher risk of developing osteoporosis, in the Italian female population. The introduction of another variable, the ER genotype, in the analysis of VDR genetic determination of BMD, may represent a useful model in the identification of patients at risk of developing a multigenic disorder like osteoporosis.

Relationship between leptin and oestrogens in healthy women.

OBJECTIVE: Leptin. a protein secreted by white adipocytes, plays a relevant role in the regulation of body weight and food intake. A possible role for sex hormones in the regulation of leptin secretion has been suggested; however, the effect of variations in oestrogen concentration on serum leptin levels has not been described so far. METHODS: In study 1, serum leptin concentrations were measured on days 3, 10, 17 and 24 of the menstrual cycle in 18 healthy, lean, regularly menstruating women, aged 18-35 years. Serum oestradiol, progesterone, testosterone. Delta4-androstenedione, dehydroepiandrosterone sulphate (DHEAS). LH and FSH concentrations were also determined. In study 2, serum leptin and oestradiol levels were measured on the 5th and 7th day of ovarian stimulation with human FSH (225 IU daily) during an in vitro fertilisation programme for infertility in 20 women aged 25-45 years. RESULTS: The results from study 1 show a physiological fluctuation of leptin levels during the menstrual cycle, which has not been described previously. Leptin levels are significantly lower in the early follicular phase. The results of study 2 show a parallel increase in serum oestrogen and leptin concentrations during FSH administration. CONCLUSIONS: The fluctuation in leptin levels during the menstrual cycle observed in study 1 is compatible with the hypothesis of a stimulatory effect of oestrogen on leptin secretion. The results of study 2 support the hypothesis of a relevant role for oestrogen in the regulation of leptin secretion. Leptin fluctuations during the menstrual cycle are consistent with reported perimenstrual variations in food craving and consumption.

Prevention of early postmenopausal bone loss with cyclical etidronate.

Cyclical etidronate has been shown to be effective in the treatment of established postmenopausal osteoporosis but less is known about its effects on early menopausal bone loss. The aim of the study was to establish the effects of cyclic etidronate therapy on spinal and proximal femoral bone mineral loss in early postmenopausal women. One hundred and seven women who were within 6 months to 3 years of the menopause were recruited into a 2-year, randomised, placebo-controlled, double-blind trial. Spinal bone mineral density was within 2 SD of the age-matched mean reference value at baseline. Bone mineral density in the lumbar spine and proximal femur was assessed by dual energy X-ray absorptiometry at baseline and thereafter at 6 monthly intervals for 2 years. Urinary collagen cross-links (deoxypyridinoline and pyridinoline) were measured at the same time points. Seventy-seven women completed the study. At the end of the treatment period, the mean bone mineral density change from baseline in the treated group was +0.14% and -0.06% in the lumbar spine and femoral neck, respectively, compared to -1.49 and -2.22 in the control group. Overall, there was a significant difference between the two groups at both these sites (p=0.01 and 0.001, respectively). No significant differences between the groups were demonstrated at the greater trochanter or Ward's triangle. The conclusion was that cyclical etidronate therapy prevents bone loss in the spine and femoral neck in early postmenopausal women. It provides a safe and effective therapeutic option for the prevention of postmenopausal osteoporosis in women who are unwilling or unable to tolerate hormone replacement therapy.

Comparison of immuno- and HPLC-assays for the measurement of urinary collagen cross-links.

Pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) are two cross-links of collagen molecules, that are present in the extracellular matrix and released during its degradation. Pyr is present in bone and cartilage, but not in significant amounts in other connective tissues and D-Pyr appears to be specific for bone tissue. Therefore, the urinary excretion of Pyr and D-Pyr might be a sensitive marker of bone matrix degradation. For the determination of urinary Pyr and D-Pyr two methods are available: a chromatographic method (HPLC) by which it is possible to measure separately Pyr and D-Pyr, and a new immunoassay which measures total free and low molecular weight pyridinoline released in the urine. We compared the results obtained by HPLC analysis of 205 urinary samples from normal subjects and patients affected by various bone disorders with those obtained by the immunoassay. The overall correlation coefficient between the results obtained by the two methods was 0.34. When calculated in a range of pyridinoline concentrations from 0 to 30, 30 to 60, and over 60 pmol/mumol creatinine the correlation coefficient was respectively -0.094, 0.38, and 0.12. The two methods yielded variable profiles in the detection of circadian rhythms and these differences did not segregate with normal or pathological conditions. We conclude that the immunoassay proposed for the determination of urinary collagen cross-links is not immediately applicable to clinical use. The improvement of the antibody specificity will probably contribute to replace the HPLC method with the immunoassay.

Ipriflavone and low doses of estrogens in the prevention of bone mineral loss in climacterium.

Estrogen replacement therapy can counteract all postmenopausal symptoms. While low estrogen doses (0.15-0.30 mg of conjugated estrogens/day) can counteract neurovegetative and psychological symptoms, higher estrogen doses (at least 0.625 mg of conjugated estrogens/day) are required to prevent bone mineral loss in postmenopausal women. However, if contra-indications to high estrogen doses exist, drugs other than estrogens can represent a suitable treatment for postmenopausal osteoporosis both alone or in combination with low estrogen doses. Experimental and clinical data have shown that ipriflavone is effective in the treatment of established postmenopausal osteoporosis. With the purpose of evaluating whether ipriflavone is able to enhance estrogen activity on bone metabolism, 133 postmenopausal women were randomly submitted to the treatment with: (1) placebo; (2) 0.15 mg/day of conjugated estrogens; (3) 0.30 mg/day of conjugated estrogens; (4) 0.15 mg/day of conjugated estrogens plus 600 mg/day of ipriflavone; (5) 0.30 mg/day of conjugated estrogens plus 600 mg/day of ipriflavone. One g/day of calcium supplementation was given to all women. In all subjects bone mineral density was measured before and after 6 and 12 months of treatment at the distal radius by dual-photon absorptiometry. A moderate decrease of bone mineral density was evidenced in women submitted to placebo or to estrogen therapy alone. By contrast, an increase of BMD was measured after 12 months of treatment in the women treated with 0.15 (not significant) or 0.30 mg/day (P < 0.01) of conjugated estrogens associated with ipriflavone. Both dosages of conjugated estrogens were able to induce a significant reduction of neurovegetative symptoms. The increase of bone density obtained with the combination of conjugated estrogens with ipriflavone demonstrates that this combination improves the effects of low estrogen doses on bone mass representing a satisfactory approach in the prevention and treatment of all symptoms related to the climacteric syndrome.

Polymorphisms of the calcitonin receptor gene are associated with bone mineral density in postmenopausal Italian women.

Recognition of a major genetic component in bone mass determination represented the basis for studies aiming to the identification of underlying major and minor genes. Bone mineral density (BMD) represents the continuous trait to be quantified in order to evaluate segregation of candidate genes with risk of osteoporosis. Polymorphisms at the vitamin D receptor (VDR), estrogen receptor, (ER), collagen type I, and interleukin 6 (IL6) gene loci have been correlated to BMD. However, in a polygenic disorder, such as osteoporosis, the number of genes expected to influence BMD is very large. In the present study we examined the presence of restriction fragment length polymorphisms (RFLPs) for the calcitonin receptor (CTR) gene in postmenopausal women. We identified a polymorphic (Tt) site at the CTR gene locus using the Taq I restriction fragment enzyme. Three genotypes were observed, whose Tt was the most frequent in our population (49.7%). In addition, Ancova analysis and Tukey's test showed that women with tt genotype had significantly lower lumbar BMD in comparison with Tt genotype (Tukey's test: p = 0.005). In conclusion, evidence of RFLPs at the CTR gene locus in Caucasian postmenopausal women of Italian origin made it possible to identify the involvement of another gene, the CTR gene, in the determination of bone mass.