A. Spinetti

Ultrasonographic bone characteristics during normal pregnancy: Longitudinal and cross-sectional evaluation

OBJECTIVE We evaluated the pattern of bone density during pregnancy by radiation-free ultrasonographic densitometry. STUDY DESIGN In a longitudinal study we measured bone mineral density in a group of 10 normal primiparous women, from the fourteenth to the thirty-eighth weeks of pregnancy. In a cross-sectional study bone mineral density was determined in a group of 85 normal primiparous women, in different weeks of pregnancy. RESULTS In the longitudinal study ultrasonographic bone density was stable in the first part of pregnancy, whereas a significant (p < 0.05) decrease was evidenced during the third trimester. A negative correlation between bone density and weeks of pregnancy (p < 0.0001) was evidenced in the cross-sectional study. CONCLUSION During physiologic pregnancy the calcium mobilization from the maternal bone stores to accomplish the fetal needs can cause a significant decrease in maternal bone density in the last trimester of gestation.

Effects of ipriflavone administration on bone mass and metabolism in ovariectomized women

The aim of the present study was to assess the effects of ipriflavone administration in the prevention of the rapid bone loss that follows ovariectomy in women. After 10–30 days from bilateral ovariectomy, patients received either the sole calcium supplementation (500 mg/day, n=16) or ipriflavone (600 mg/day, n=16) in addition to the same daily calcium supplement for 12 months. In calcium-treated subjects urinary hydroxyproline excretion, serum alkaline phosphatase and plasma bone Gla protein levels showed a substantial (p<0.01) increase, while radial bone density significantly (p<0.01) decreased 6 months after surgery. In ipriflavone treated group the patterns of biochemical markers indicated that ipriflavone can restrain the bone remodeling processes and radial bone density showed no significant modification during the 12 month study period. These results demonstrate that ipriflavone administration prevents the rapid bone loss that follows ovariectomy. Thus, ipriflavone can represent an actractive alternative for the prevention of osteoporosis in postmenopausal women who present contraindications to the estrogen replacement therapy.

Effects of hormonal replacement therapy on plasma sex hormone-binding globulin, androgen and insulin-like growth factor-1 levels in postmenopausal women

Plasma sex hormone-binding globulin (SHBG) levels are important in the regulation of plasma free and albumin-bound androgens and estrogens. In postmenopausal women associated to the decrease of estrogen production, a decrease of plasma SHBG levels occurs. Hormone replacement therapy (HRT) in postmenopausal women modulates plasma SHBG levels, in relationship with the different regimens and routes of administration. The present study aimed to compare the effect of different HRT on plasma SHBG levels in relationship with the changes of plasma androgen [dehydroepiandrosterone sulphate (DHEAS), testosterone (T), androstenedione (A)] and insulin-like growth factor-1 (IGF-1) levels. In a retrospective study 443 postmenopausal women were studied and divided into 2 groups. The group 1 (n=170) was subdivided in 4 groups of women as follows: A) treated with transdermal 17-β estradiol + medroxyprogesterone acetate, B) treated with oral conjugated estrogens, C) treated with sequential HRT (estradiol valerate (EV) + norgestrel), and D) treated with a combined HRT (micronized estradiol (E2) + noretisterone acetate). Women of group 2 (n=273) did not receive HRT and served as controls. All groups of women treated with different HRT showed plasma estradiol levels significantly higher than controls (p<0.01), showing the highest values in women treated with oral HRT. Plasma SHBG levels were not significantly different between patients treated with transdermal 17-β estradiol + medroxyprogesterone acetate and controls. On the other hand, all the groups of patients treated with oral conjugated estrogen with or without progestagens showed plasma SHBG levels significantly higher than controls (p<0.01). Plasma SHBG levels were higher in the group treated with estrogen alone than in groups of women treated with sequential or combined HRT. Plasma DHEAS, T and A levels in patients treated with different HRT regimens were in the same range of levels as control women. Plasma IGF-1 levels were not significantly affected by the various HRT regimens and remained in the same range as controls. In conclusion, plasma SHBG levels increase following oral HRT while are not affected by transdermal HRT. Plasma IGF-1 and androgen levels are not influenced from oral or transdermal HRT.

Menopause and the central nervous system: intervention options.

The central nervous system is an important target for sex steroid hormones. During the climateric period the rapid decline of gonadal steroids causes neuroendocrine changes in different areas of the brain. The failure of gonadal hormone production brings specific symptoms due to the central nervous system derangement. At the hypotalamic level estrogen withdrawal gives rise to vasomotor symptoms, eating behavior disorders and altered blood pressure control. Psychological disturbances such as depression, anxiety, irritability and mood fluctuation are related to estrogen-induced changes in the lymbic system. The hypothesis of specific neuroanatomical and neurophysiological effects of estrogen on the brain may also explain the correlation between estrogen deficiency and cognitive disturbances such as Alzheimers type dementia (AD). The increasing interest in the influence of sex steroids on brain function has focused attention on hormonal replacement therapy. Clinical and epidemiological studies have demonstrated that estrogen therapy exerts a positive effect on vasomotor instability and improves psychological disturbances. The positive effects of estrogen on mood are probably related to its stimulatory action on adrenergic and serotoninergic tone. Estrogen may influence the cognitive function through different biological actions. Estrogen administration increases total cerebral and cerebellar blood flow, cerebral glucose administration and improves cholinergic tone, a key neurotransmitter in learning and memory. The evidence suggests that hormone replacement therapy may reduce the relative risk of developing AD. Progestagens and androgen may also have a role in the control of mood disorders. At present, few data are available regarding the influence that selective estrogen receptor modulators, a new class of compounds, can exert on the brain.

Hormone replacement therapy in perimenopausal women with a low dose oral contraceptive preparation: effects on bone mineral density and metabolism.

In a 2-year longitudinal, calcium-controlled study we evaluated bone density and metabolism in perimenopausal women with initial ovarian failure, and the effects of hormone replacement with a low dose oral contraceptive preparation (OC). In perimenopausal oligomenorrhoic women (n = 16) a significant (P < 0.01) increase in cycle length and plasma FSH levels as well as a parallel decrease in plasma estradiol levels (P < 0.01) were evident. In this group, despite the calcium supplementation (500 mg/day), a significant (P < 0.001) increase in the biochemical markers of bone remodelling paralleled a significant (P < 0.001) decrease (-3.4% after 24 months) in bone density. Conversely, in premenopausal oligomenorrhoic women treated with a low dose oral contraceptive (OC) formulation (30 mcg ethinyl estradiol plus 75 mcg gestodene, n = 16), bone markers showed a significant (P < 0.01) decrease, that paralleled a slight but significant (P < 0.01) increase (+1.71%) in bone density. These data suggest that premenopausal administration of OC can prevent the acceleration of bone turnover and reverse the decrease in bone density that follows the premenopausal impairment of ovarian function.

Endocrine ,neuroendocrine and behavioral effects of oral dehydroepiandrosterone sulfate supplementation in postmenopausal women

Aging in women and men is characterized by a progressive decline of circulating dehydroepiandrosterone (DHEA) levels and its sulfate ester (DHEAS). The improvement of wellbeing described in postmenopausal women treated with DHEA suggests that this steroid may exert specific actions on the central nervous system (CNS). The postmenopausal period is associated with several neuroendocrine modifications. The decrease of circulating levels of beta-endorphin is considered a hormonal marker of those changes. The aim of the present study was to investigate neuroendocrine and behavioral effects of three months of DHEAS supplementation in postmenopausal women. Postmenopausal women (n = 22) were divided in three groups: the first group was treated with oral DHEAS (n = 8) (50 mg/day), the second treated with the same dose of oral DHEAS + transdermal estradiol (n = 8) (DHEAS) 50 mg/day, estradiol 50 micrograms/patch) and the third with transdermal estradiol alone (n = 6) (50 micrograms/day). Before and after 1, 2 and 3 months of therapy, the following circulating steroid and protein hormone levels were evaluated: DHEA, DHEAS, androstenedione, testosterone, estrone, estradiol, 17-hydroxyprogesterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), luteinizing hormone (LH), beta-endorphin, growth hormone (GH) and cortisol, and a Kupperman score was performed. Before and after treatments, plasma beta-endorphin levels were evaluated in response to three neuroendocrine tests: (a) clonidine, an alpha 2-presynaptic adrenergic agonist (1.25 mg i.v.) (b) naloxone, an opioid receptor antagonist (4 mg i.v.) and (c) fluoxetine, a serotonin selective reuptake inhibitor (30 mg p.o.). In both groups of women treated with DHEAS, mean basal serum DHEA, DHEAS, androstenedione, and testosterone levels significantly increased after treatment, while no changes were shown in the group receiving estradiol alone. Serum estradiol, estrone, GH and plasma beta-endorphin levels significantly increased progressively for the three months of treatment, with higher levels for estrone and estradiol in subjects receiving estradiol alone or plus DHEAS. Serum SHBG, cortisol, and 17-hydroxyprogesterone did not show significant variations under any treatment. Serum LH and FSH levels showed a significant decrease in groups treated with estradiol alone or plus DHEAS at the second and third months. The Kupperman score showed that all treatments were associated with similar and progressive improvement. Before therapy clonidine, naloxone and fluoxetine stimuli failed to modify circulating beta-endorphin levels. After each of the treatments, the beta-endorphin response was completely restored and was similar, independent of the kind of therapy. Restoration of the beta-endorphin response to specific stimuli suggests that DHEAS and/or its active metabolites modulates the neuroendocrine control of pituitary beta-endorphin secretion, which may support the therapeutic efficacy of the DHEAS on behavioral symptoms.

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

The neuroendocrine and clinical effects of transdermal 17 beta-estradiol (rated at 50 micrograms/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 less than 0.01) and the enhancement of the hypothermic effect (P less than 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 less than 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.

Bone loss in perimenopausal women: a longitudinal study

A longitudinal evaluation of bone mineral density (BMD) and metabolism was performed in premenopausal women. During the 2-year observation period, the menstrual pattern, plasma estradiol and FSH levels as well as the values of bone markers and BMD did not show any significant modification in a group of eumenorrhoic women (n = 37). Conversely, in age-matched oligomenorrhoic women (n = 37) a significant (P < 0.05) increase in the cycle length with a concomitant significant (P < 0.05) increase in circulating plasma FSH and parallel decrease of plasma estradiol levels (P < 0.05) was evident. In this group a significant (P < 0.05) increase in both urinary excretion of OH-P/Cr and plasma BGP levels paralleled a significant (P < 0.05) decrease in radial BMD. These data suggest that premenopausal impairment of ovarian function can lead to a bone loss in a significant proportion of women in which prevention should be considered before menopause.

Lack of any estrogenic effect of ipriflavone in postmenopausal women

Estrogen replacement therapy (ERT) has been demonstrated to prevent osteoporosis in postmenopausal women (PMW). However, several contraindications exist for ERT and many PMW cannot be treated. It has also been shown that too low doses of ERT are able to exert therapeutical effects on some climacteric symptoms but not on bone and compounds exerting synergic actions with ERT on bone without effects on other organs could be useful. The isoflavone derivative, ipriflavone, seems to have this effect but data are lacking on its endocrine effect in humans; thus, this study was undertaken to clarify in PMW whether ipriflavone exerts estrogenic activity. Evaluation of LH and FSH secretion during a 24-h period was performed in a group of 15 PMW after a single oral dose of 600 or 1,000 mg of ipriflavone or placebo, and after 7, 14 and 21 days of oral treatment with ipriflavone 600 mg and 1,000 mg/daily, administered in three divided doses. LH secretion was also evaluated during naloxone infusion before and after 21 days of ipriflavone, placebo or conjugated estrogen treatment (0.625 mg/day; CE). LH response to NAL treatment was absent during ipriflavone and placebo such as it was observed before treatments. By contrast, a significant increase of LH plasma levels was measured during naloxone infusion in CE-treated women. This result demonstrates that ipriflavone is unable to exert the same effects that estrogens do in PMW. In addition, no changes like in placebo group were seen on vaginal cytology in this group of subjects after 21 days, whereas a significant increase of superficial vaginal cells was observed after 21 days of CE treatment. These data confirm that ipriflavone is devoid of estrogenic activity also in humans and its efficacy in the prevention of osteoporosis in PMW should be ascribed to different mechanisms of action in comparison to estrogens.

Ipriflavone prevents the bone mass reduction in premenopausal women treated with gonadotropin hormone-releasing hormone agonists.

In the present study we assessed the effects of ipriflavone in the prevention of increased bone turnover and the rapid bone loss that follows medical induced hypogonadism caused by the administration of a gonadotropin hormone-releasing hormone agonist (GnRH-A). In a double blind, placebo-controlled study, ipriflavone (600 mg/day, tdd (three divided doses)) or identical placebo tablets were given with 500 mg/day of calcium to patients treated with 3.75 mg leuproreline acetate every 30 days, for 6 months. In placebo-treated subjects (n = 39), urinary hydroxyproline excretion and plasma bone GLA protein levels showed a substantial (P < 0.01) increase, while spine bone density and total body bone density significantly (P < 0.01) decreased after 3 and 6 months of GnRH-A administration. Conversely, in ipriflavone treated group (n = 39), no significant difference in bone markers and bone density was evidenced. These data indicate that ipriflavone can restrain the bone remodeling processes and prevent the rapid bone loss that follows medical induced hypogonadism. Thus, ipriflavone administration can be of value in the prevention of osteopenia in women treated with GnRH-A.