Radiotherapy-induced malignancies in breast cancer patients with TP53 pathogenic germline variants (Li–Fraumeni syndrome)

Familial Cancer - The risk of radiotherapy-induced malignancies (RIMs) is a concern when treating Li–Fraumeni syndrome (LFS) or Li–Fraumeni Like (LFL) patients. However, the type of...     

Neuroendocrine and clinical effects of transdermal 17β-estradiol in postmenopausal women

The neuroendocrine and clinical effects of transdermal 17β-estradiol (rated at 50 μg/day; TTS 50) were studied in 40 postmenopausal women; ten additional postmenopausal women did not receive any drugs. The changes in LH and rectal temperature induced by the infusion of the opioid antagonist naloxone (10 mg i.v. bolus plus 10 mg/h for 4 h) were used to evaluate the central activity of endogenous opioid peptides. TTS 50 increased opioid activity, as evidenced by the restoration of the LH response (P < 0.01) and the enhancement of the hypothermic effect (P < 0.05) of naloxone. A greater reduction in hot flushes was observed in TTS 50-treated subjects than in untreated women, with the maximal effect of TTS 50 achieved after 3 months of therapy. TTS 50 did not modify the concentrations of circulating lipids, glucose or liver enzymes but reduced the biochemical parameters indicative of bone reabsorption. Bone density of the distal radius significantly increased during TTS 50 (P < 0.02), reaching its maximum value after 6 months of therapy. Thereafter bone density declined, but more slowly than in untreated women.

Our data suggest that TTS 50 has marked neuroendocrine effects, that it diminishes the incidence of hot flushes and reduces bone demineralization. By contrast, it has a very little, if any, metabolic impact on the liver or on glucose and lipid metabolism.     

Administration of tibolone decreases 24 h heart rate but not blood pressure of post-menopausal women

OBJECTIVE: Elevation of blood pressure and heart rate increase the risk of cardiovascular disease. Administration of estrogens does not affect heart rate but may decrease 24 h blood pressure. In this study, we tested the effect of the estro-progestogenic compound tibolone. METHODS: Thirty healthy, post-menopausal women were randomized to receive placebo (n = 15) or tibolone, at the commonly prescribed dose of 2.5 mg per day (n = 15). Before and after 6 months of treatment, in each woman blood pressure and heart rate were monitored every 30 min for 41 h by an ambulatory device. Valuable readings were those collected from 8:00 a.m. of the second day to 8:00 a.m. of third day. Analyses were performed of 24 h, day-time (7:00 a.m.-11:00 p.m.) and night-time (11:00 p.m.-7:00 a.m.) values. Day to night difference was also calculated. Results: Placebo did not modify 24h, day-time, and night-time blood pressure or heart rate values. Day-night differences were also not affected by placebo. Similarly to placebo, tibolone administration did not modify any of the blood pressure parameters taken into consideration. By contrast, a significant decline of 24 h heart rate (73.2 +/- 2.3 beats/min versus 69.3 +/- 1.7 beats/min; P < 0.0008) was observed. The effect was significant both at day (76.6 +/- 2.4 beats/min versus 72.1 +/- 1.9 beats/min; P < 0.0001) and night (65.8 +/ 2.6 beats/min versus 62.4 +/- 1.9 beats/min; P < 0.05). Day-night blood pressure and heart rate differences were not affected by tibolone. CONCLUSIONS: In post-menopausal women, administration of tibolone does not influence 24 h blood pressure but reduces heart rate.     

Transdermal administration of estradiol and norethisterone: effect on the uterus and uterine arteries

OBJECTIVE: To evaluate the short- and long-term effect on the uterus, endometrium, and vascular reactivity of uterine arteries of sequential transdermal estradiol (50 microg/day) and norethisterone (0.25 mg/day in the last 14 days of each cycle). DESIGN: An intravaginal ultrasound evaluation was performed in 48 postmenopausal women before and at the 3rd and 12th month of treatment, during the last 3 days of both estradiol alone and estradiol plus norethisterone. An endometrial biopsy was also performed before and at the end of treatment. In 11 participants, intravaginal ultrasound and endometrial biopsy were repeated after 48 months of treatment. RESULTS: Uterine volume (33.7 +/- 3.3 cm3 to 56.8 +/- 3.7 cm3; p = 0.001) and endometrial thickness (3.07 +/- 0.48 mm to 5.74 +/- 0.41 mm; p = 0.001) increased within 3 months, with no further increases. Thickness was similar in the estradiol and estradiol-norethisterone phase. Endometrial hyperplasia was found in one participant at 12 months of treatment. A significant decrease (p = 0.002) in the pulsatility index of uterine arteries was observed only during the estradiol phase. After 48 months of treatment, the pulsatility index of uterine arteries was lower than at baseline (2.78 +/- 0.24 vs. 2.23 +/- 0.33; p = 0.044) even when evaluated in the combined phase. CONCLUSIONS: The transdermal administration of sequential estradiol and norethisterone reduces uterine artery resistance and induces a self-limiting growth of the uterus and endometrium.     

Kava-Kava administration reduces anxiety in perimenopausal women

OBJECTIVE: Disturbances of mood, such as anxiety and depression, increase in the perimenopausal period. Hormone replacement therapy or neuroactive drugs represent useful treatments for these disturbances but may be contraindicated or not accepted. Herein it was investigated the efficacy of Kava-Kava, an extract of Piper Methysticum, on mood of perimenopausal women. DESIGN: A 3-months randomized prospective open study investigating in perimenopausal women modifications induced by calcium supplementation (control; n=34), calcium plus Kava-Kava at the dose of 100 mg/day (n=15) or calcium plus Kava-Kava at the dose 200 mg/day (n=19). Anxiety was evaluated by the State Trait Anxiety Inventory (STAI); depression by the Zung's scale (SDS), and climacteric symptoms by the Greene's scale. Evaluations were performed at baseline and after 1 and 3 months. RESULTS: In the control group during the 3 months, anxiety, depression and climacteric symptoms tended to decline, but not significantly. During Kava-Kava anxiety declined (P<0.001) at 1 (-3.8+/-1.03) and 3 (-5.03+/-1.2) months, depression declined at 3 months (-5.03+/-1.4; P<0.002) and climacteric score declined (P<0.0006) at 1 (-2.87+/-1.5) and 3 (-5.38+/-1.3) months. Only the decline of anxiety induced by Kava-Kava was significantly greater than that spontaneously occurring in controls (P<0.009). CONCLUSIONS: The present data indicate that, in perimenopausal women, administration of Kava-Kava induces an improvement of mood, particularly of anxiety.     

Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women

OBJECTIVE: The effect of melatonin on human carbohydrate metabolism is not yet clear. We investigated whether melatonin influences glucose tolerance and insulin sensitivity in aged women. PATIENTS: Twenty-two postmenopausal women of whom 14 were on hormone replacement therapy. DESIGN: After an overnight fast, at 0800 hours on two nonconsecutive days, placebo or melatonin (1 mg) were administered randomly and in a double blind fashion. Forty-five minutes later, an oral glucose tolerance test (75 g; OGTT) was performed in 13 women. In another nine women insulin-dependent (Si) and -independent (Sg) glucose utilization was tested by a frequently sampled intravenous glucose tolerance test (FSIGT). RESULTS: Areas under the response curve to OGTT (AUC) for glucose (1420 +/- 59 vs. 1250 +/- 55 mmol x min/l; P < 0.01), and C-peptide (42,0980 +/- 45,320 vs. 33,528 +/- 15,779 pmol x min/l; P < 0.02) were higher following melatonin than placebo, while Si values were lower (2.6 +/- 0.28 units vs. 3.49 +/- 0.4 units; P < 0.03). Si modifications induced by melatonin were inversely related to Si values of the placebo day (r(2) = 0.538; P < 0.025). CONCLUSIONS: The present results indicate that in aged women administration of 1 mg of melatonin reduces glucose tolerance and insulin sensitivity. The present data may have both physiological and clinical implications.     

Effects of the dopamine antagonist veralipride on hot flushes and luteinizing hormone secretion in postmenopausal women

The effects on hot flushes of the dopamine antagonist Veralipride versus placebo were investigated in a randomized double-blind study of postmenopausal healthy women (N = 20 in each group). Cutaneous temperature recording and plasma LH pulsatility were studied in eight patients from each group. Veralipride administration (100 mg/day for 30 days) induced a significant (P less than .01) reduction in vasomotor symptoms and was more effective (P less than .05) than placebo. Treatment was followed by the expected increase (P less than .001) in plasma prolactin levels and by a significant decrease (P less than .05) in mean plasma LH. A significant reduction (P less than .01) was observed in objectively recorded hot flushes after Veralipride treatment, whereas there was no significant change in the characteristics of LH pulsatility. Infusion of the opioid antagonist naloxone (N = 5) induced a significant (P less than .01) increase in LH secretion after Veralipride administration. These results suggest that the endogenous opioid system may mediate the endocrine and clinical effects of long-term Veralipride treatment.     

Neutral effect of prolonged transdermal hormone therapy on liver function of postmenopausal women with chronic active hepatitis

OBJECTIVE: To test whether transdermal hormone therapy can be safely administered to postmenopausal women with chronic viral hepatitis B and/or C. DESIGN: Eighty-one postmenopausal women with chronic viral hepatitis B and/or C and with severe vasomotor symptoms were treated for 5 years with transdermal estradiol (50 microg/day) continuously and with transdermal norethisterone (250 microg/day) for 14 days of every 28-day cycle. Another 95 women with viral chronic hepatitis but without climacteric symptoms were used as controls. Liver enzymes (glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, gamma-glutamine-transferase, and alkaline phosphatase) were measured every year. RESULTS: At baseline, liver enzymes were similar in the two groups, with the exception of gamma-GT, which was slightly higher in untreated women (P < 0.01). Liver enzymes did not significantly vary with time in hormone-treated and untreated women. No significant difference was observed between the two groups. CONCLUSIONS: Transdermal estradiol and norethisterone can be safely administered for a prolonged period to postmenopausal women with chronic viral B and/or C hepatitis.     

Comparison of the effect of oral and transdermal hormone therapy on fasting and postmethionine homocysteine levels

OBJECTIVE: To compare the modifications on basal and post-methionine homocysteine (Hcy) levels induced by transdermal vs. oral continuous combined hormone therapy (HT). DESIGN: Prospective randomized study. SETTING: Outpatient service at university hospital. PATIENT(S): Twenty-four healthy postmenopausal women. INTERVENTION(S): Six-month administration of transdermal (50 microg/d of E(2) and 140-170 microg/d of norethisterone [NET] acetate; n = 12) or oral (2 mg of E(2) and 1 mg of NET acetate; n = 12) HT. MAIN OUTCOME MEASURE(S): Fasting levels of Hcy, cysteine (Cys), folate, and vitamin B12. Post-methionine Hcy concentrations. RESULT(S): During HT, a slight decrease of fasting Hcy (8.9 [6.7; 15.2] micromol/L vs. 8.3 [4.9; 12.0] micromol/L) and fasting Hcy/Cys, a possible index of Hcy trans-sulfuration (0.061 [0.039; 0.107] micromol/L vs. 0.048 [0.032; 0.093] micromol/L) was observed. Modifications were similar in the transdermal and oral group. Net decreases of Hcy and Hcy/Cys observed during HT were related linearly to pretreatment values (r = 0.821 and r = 0.775, respectively), and were significant for Hcy above, but not below, 9 micromol/L. Transdermal (33.5 [27.5; 75.9] micromol/L vs. 28.4 [17.4; 48.9] micromol/L) or oral HT (36.1 [17.7; 74.8] micromol/L vs. 29.9 [17.5; 50.3] micromol/L), decreased, similarly, post-methionine Hcy levels. CONCLUSION(S): Similarly to oral, transdermal HT reduces post-methionine Hcy and fasting Hcy when it is elevated.