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Gonadotropin hormone releasing hormone agonists alter prefrontal function during verbal encoding in young women

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Abstract

Gonadotropin hormone releasing hormone agonists (GnRHa) are commonly used in clinical practice to suppress gonadal hormone production in the management of various gynaecological conditions and as a treatment for advanced breast and prostate cancer. Animal and human behavioural studies suggest that GnRHa may also have significant effects on memory. However, despite the widespread use of GnRHa, the underlying brain networks and/or stages of memory processing that might be modulated by GnRHa remain poorly understood. We used event-related functional magnetic resonance imaging to examine the effect of GnRHa on verbal encoding and retrieval. Neuroimaging outcomes from 15 premenopausal healthy women were assessed at baseline and 8 weeks after Gonadotrophin Releasing Hormone analogue (GnRHa) treatment. Fifteen matched wait-listed volunteers served as the control group and were assessed at similar intervals during the late follicular phase of the menstrual cycle. GnRHa was associated with changes in brain response during memory encoding but not retrieval. Specifically, GnRHa administration led to a change in the typical pattern of prefrontal activation during successful encoding, with decreased activation in left prefrontal cortex, anterior cingulate, and medial frontal gyrus. Our study suggests that the memory difficulties reported by some women following GnRHa, and possibly at other times of acute ovarian hormone withdrawal (e.g. following surgical menopause and postpartum), may have a clear neurobiological basis; one that manifest during encoding of words and that is evident in decreased activation in prefrontal regions known to sub-serve deep processing of to-be-learned words.

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... The Study of Women's Health Across the Nation (SWAN) also reported a cross-sectional association between self-reported forgetfulness and being perimenopausal 2 . Forgetfulness was common in middle age: in this sample of 12,425 women aged [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55] years, unadjusted for sociodemographic factors, 31% of premenopausal, 44% of early or late perimenopausal and 42% of naturally menopausal women endorsed forgetfulness. After adjustment for race/ethnicity, age, education, economic hardship, marital status, parity, body size, health habits and symptoms of anxiety, depression and poor sleep, perimenopausal women were 1.4 times more likely to report forgetfulness than were premenopausal women. ...
... The impact of ovarian hormone withdrawal on brain function and the importance of the cholinergic system in the context of ovarian hormone withdrawal are evident in a series of neuroimaging studies by Michael Craig and colleagues [48][49][50] . In these studies, healthy premenopausal women underwent pharmacological ovarian hormone suppression with leuprolide acetate, and given a verbal memory task. ...
... In these studies, healthy premenopausal women underwent pharmacological ovarian hormone suppression with leuprolide acetate, and given a verbal memory task. Hormone suppression produced decreased activation in the left prefrontal cortex, anterior cingulate, and medial frontal gyrus 49 . A subsequent study demonstrated that brain function returned to baseline when ovarian hormone levels returned to normal 48 . ...
Article
The impact of perimenopause on cognition seems to be characterized by an absence of improved scores rather than a decline. In the SWAN, the perimenopausal decrement in cognitive performance was not accounted for; however, increases in anxiety and depressive symptoms had independent, unfavorable effects on performance. Estradiol has been found to protect against changes resulting from serotonin withdrawal and defend against changes from cholinergic depletion. There is support for the critical timing hypothesis--that estrogen benefits cognitive function when instituted early, but not later. The menopausal transition may affect cognitive function in older age owing to worsened cardiovascular risk factors.
... Previous studies mainly investigated the influence of shortterm GnRHa on brain activity in young women, suggesting altered brain activity in the frontal and temporal cortices which belong to default mode network (38)(39)(40). There is a possible reason for this inconsistent brain region results, given the differences in duration of treatment and age between the participants of earlier studies and our study. ...
... Thus, the lack of frontal and temporal results in present study may be attributed to the modulation of the visual network prior to default mode network by GnRHa. Besides, the effects of GnRHa on the brain regions of primary systems, including the visual system may become apparent only after long-term treatment (40). ...
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Purpose: The pubertal growth suppressive effects of gonadotropin hormone releasing hormone agonists (GnRHa) are well-known, although it remains unclear if long-term GnRHa treatment influences the brain function of treated children. The present study investigated the differences in the homotopic resting-state functional connectivity patterns in girls with idiopathic central precocious puberty (ICPP) with and without GnRHa treatment using voxel-mirrored homotopic connectivity (VMHC). Methods: Eighteen girls with ICPP who underwent 12 months of GnRHa treatment, 40 treatment-naïve girls with ICPP, and 19 age-matched girls with premature thelarche underwent resting-state functional magnetic resonance imaging using a 3T MRI. VMHC method was performed to explore the differences in the resting-state interhemispheric functional connectivity. The levels of serum pubertal hormones, including luteinizing hormone (LH), follicular-stimulating hormone, and estradiol, were assessed. Correlation analyses among the results of clinical laboratory examinations, neuropsychological scales, and VMHC values of different brain regions were performed with the data of the GnRHa treated group. Results: Significant decreases in VMHC of the lingual, calcarine, superior temporal, and middle frontal gyri were identified in the untreated group, compared with the control group. Medicated patients showed decreased VMHC in the superior temporal gyrus, when compared with the controls. Compared to the unmedicated group, the medicated group showed a significant increase in VMHC in the calcarine and middle occipital gyrus. Moreover, a positive correlation was observed between basal LH levels and VMHC of the middle occipital gyrus in medicated patients. Conclusions: These findings indicate that long-term treatment with GnRHa was associated with increased interhemispheric functional connectivity within several areas responsible for memory and visual process in patients with ICPP. Higher interhemispheric functional connectivity in the middle occipital gyrus was related to higher basal LH production in the girls who underwent treatment. The present study adds to the growing body of research associated with the effects of GnRHa on brain function.
... It is clear that oestrogen has an important role in cognitive functioning (Sherwin, 2012) but few studies have examined the effect of adjuvant endocrine therapy for breast cancer on cognitive function (Phillips et al, 2010(Phillips et al, , 2011aSchilder et al, 2010;Ganz et al, 2014) and none has assessed the impact of OFS. OFS results in very-low circulating oestrogen levels and some (Varney et al, 1993;Grigorova et al, 2006;Craig et al, 2007), but not all (Owens et al, 2002;Schmidt et al, 2013) data from non-oncological settings suggest that OFS with gonadotropin-releasing hormone agonists (GnRH) agents impair cognition and that this impairment can be reversed with add-back oestrogen (Sherwin and Tulandi, 1996). It has also been reported that surgical menopause adversely affects cognition (Rocca et al, 2007;Ryan et al, 2014). ...
... The only cognitive task for which performance of women randomised to OFS deteriorated significantly more than those randomised to tamoxifen alone was a test of verbal learning and memory, the ISLT. Some studies have suggested that verbal memory is particularly affected by OFS in non-oncological settings (Craig et al, 2007); however, we did not find a difference between the OFS and tamoxifen alone groups in terms of amount of deterioration in another measure of verbal memory, the delayed ISLT. Previous studies in this field have focussed on tamoxifen and the aromatase inhibitors, nevertheless the impact of these drugs on cognitive function remains poorly understood (Buwalda and Schagen, 2013). ...
Article
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Background: To examine the effect on cognitive function of adjuvant ovarian function suppression (OFS) for breast cancer. Methods: The Suppression of Ovarian Function (SOFT) trial randomised premenopausal women with hormone receptor-positive breast cancer to 5 years adjuvant endocrine therapy with tamoxifen+OFS, exemestane+OFS or tamoxifen alone. The Co-SOFT substudy assessed objective cognitive function and patient reported outcomes at randomisation (T0), and 1 year later (T1); the primary endpoint was change in global cognitive function, measured by the composite objective cognitive function score. Data were compared for the pooled tamoxifen+OFS and exemestane+OFS groups vs the tamoxifen alone group using the Wilcoxon rank-sum test. Results: Of 86 participants, 74 underwent both T0 and T1 cognitive testing; 54 randomised to OFS+ either tamoxifen (28) or exemestane (26) and 20 randomised to tamoxifen alone. There was no significant difference in the changes in the composite cognitive function scores between the OFS+ tamoxifen or exemestane groups and the tamoxifen group (mean±s.d., -0.21±0.92 vs -0.04±0.49, respectively, P=0.71, effect size=-0.20), regardless of prior chemotherapy status, and adjusting for baseline characteristics. Conclusions: The Co-SOFT study, although limited by small samples size, provides no evidence that adding OFS to adjuvant oral endocrine therapy substantially affects global cognitive function.British Journal of Cancer advance online publication 19 April 2016; doi:10.1038/bjc.2016.71 www.bjcancer.com.
... In non-depressed peri-and postmenopausal women, estradiol therapy increases verbal recall, a prefrontalmediated process, and increases frontal cortex activation (Joffe et al., 2006). Interestingly, administration of a GnRH agonist to healthy premenopausal women decreases prefrontal activation and impairs verbal memory (Craig et al., 2007), providing further support for an important role for estrogens in the prefrontal cortex (Table 2). ...
... This effect of estrogens on postmenopausal cognitive ability has also been illustrated in rhesus macaques (Rapp et al., 2003). Finally, administration of GnRH to suppress ovarian function resulted in a decrease in activity within the prefrontal cortex, a decrease in memory performance, and a decrease in quality of mood (Craig et al., 2007;Grigorova et al., 2006). Further research is required to clarify the relationship between the prefrontal cortex and estrogens in hormonedependent mood disorders. ...
... The neural effects of abrupt estrogen loss in pre-menopausal women have been studied prospectively with gonadotropin hormone releasing hormone (GnRH) agonists. These studies generally show that estrogen ablation is associated with reversible decreased task-related activation (Berman et al. 1997;Craig et al. 2007;). However, the neural effects of CIA remain unclear. ...
... Studies of longer-term survivors with a history of CTx have demonstrated lower activation in task-related regions (de Ruiter et al. 2011;Kesler et al. 2011). Prospective studies of pre-menopausal women who undergo abrupt estrogen suppression with gonadotropin releasing hormone (GnRH) agonists have shown globally attenuated task-related blood flow on PET in the context of maintained task performance (Berman et al. 1997), and decreased frontal fMRI activation during memory encoding with a trend toward worse performance on the subsequent recognition test (Craig et al. 2007). It is notable that in the GnRH agonist studies, estrogen is still being suppressed at the time of scanning, while at M1 in the current study, ovarian function may be starting to resume after CIA and several patients were using tamoxifen, which also affects estrogen function. ...
Article
Chemotherapy-induced amenorrhea (CIA) often occurs in pre- and peri-menopausal BC patients, and while cancer/chemotherapy and abrupt estrogen loss have separately been shown to affect cognition and brain function, studies of the cognitive effects of CIA are equivocal, and its effects on brain function are unknown. Functional MRI (fMRI) during a working memory task was used to prospectively assess the pattern of brain activation and deactivation prior to and 1 month after chemotherapy in BC patients who experienced CIA (n = 9), post-menopausal BC patients undergoing chemotherapy (n = 9), and pre- and post-menopausal healthy controls (n = 6 each). Neurocognitive testing was also performed at both time points. Repeated measures general linear models were used to assess statistical significance, and age was a covariate in all analyses. We observed a group-by-time interaction in the combined magnitudes of brain activation and deactivation (p = 0.006): the CIA group increased in magnitude from baseline to post-treatment while other groups maintained similar levels over time. Further, the change in brain activity magnitude in CIA was strongly correlated with change in processing speed neurocognitive testing score (r = 0.837 p = 0.005), suggesting this increase in brain activity reflects effective cognitive compensation. Our results demonstrate prospectively that the pattern of change in brain activity from pre- to post-chemotherapy varies according to pre-treatment menopausal status. Cognitive correlates add to the potential clinical significance of these findings. These findings have implications for risk appraisal and development of prevention or treatment strategies for cognitive changes in CIA.
... In contrast to the randomized controlled trials of estrogen therapy, observational studies more consistently report that estrogen therapy in young perimenopausal women has long term beneficial effects on cognitive function and affords a small reduction in the risk of dementia (Bagger et al. 2005;Henderson et al. 2005;MacLennan et al. 2006;Whitmer et al. 2011;Yaffe et al. 1998;Zandi et al. 2002). The remaining evidence suggesting a significant effect of estradiol on cognitive function to a large degree is derived from clinic-based studies of hypogonadal women in whom surgical oophorectomy was performed (Phillips et al. 1992;Sherwin 1988) or a GnRH agonist was administered to suppress ovarian function as part of a treatment for an underlying gynecologic condition (Craig et al. 2007;Grigorova et al. 2006;Palomba et al. 2004;Sherwin et al. 1996;Varney et al. 1993). Although the specific cognitive function that is reported to decline during hypogonadism varies across studies, a decline in some aspect of cognitive performance is consistently observed during induced hypogonadism (and in some studies, a subsequent improvement in performance after estradiol therapy). ...
... Several previous reports examined the effects of GnRH agonist-induced hypogonadism, and in some E replacement, on cognition in younger women receiving treatment for uterine fibroids or endometriosis (Grigorova et al. 2006;Sherwin et al. 1996). In contrast to our data, (Craig et al. 2007;Palomba et al. 2004;Varney et al. 1993) the majority of these studies observed a significant decline in cognitive performances during hypogonadism compared with baseline, including measures of verbal memory, working memory, and visual recognition, and an improvement in several of these measures (e.g., verbal memory) in those women receiving E (but not in those receiving placebo) while on GnRH agonist. Our findings are consistent with those of Owens (2002), who also studied asymptomatic healthy women at baseline and under conditions of GnRH agonist-induced ovarian suppression of four months duration and, in half of the women, after estradiol replacement. ...
Article
Gynecology clinic-based studies have consistently demonstrated that induced hypogonadism is accompanied by a decline in cognitive test performance. However, a recent study in healthy asymptomatic controls observed that neither induced hypogonadism nor estradiol replacement influenced cognitive performance. Thus, the effects of induced hypogonadism on cognition might not be uniformly experienced across individual women. Moreover, discrepancies in the effects of hypogonadism on cognition also could suggest the existence of specific risk phenotypes that predict a woman's symptomatic experience during menopause. In this study, we examined the effects of induced hypogonadism and ovarian steroid replacement on cognitive performance in healthy premenopausal women. Ovarian suppression was induced with a GnRH agonist (Lupron) and then physiologic levels of estradiol and progesterone were reintroduced in 23 women. Cognitive tests were administered during each hormone condition. To evaluate possible practice effects arising during repeated testing, an identical battery of tests was administered at the same time intervals in 11 untreated women. With the exception of an improved performance on mental rotation during estradiol, we observed no significant effects of estradiol or progesterone on measures of attention, concentration, or memory compared with hypogonadism. In contrast to studies in which a decline in cognitive performance was observed in women receiving ovarian suppression therapy for an underlying gynecologic condition, we confirm a prior report demonstrating that short-term changes in gonadal steroids have a limited effect on cognition in young, healthy women. Differences in the clinical characteristics of the women receiving GnRH agonists could predict a risk for ovarian steroid-related changes in cognitive performance during induced, and possibly, natural menopause.
... These findings therefore suggested a biological mechanism through which ovarian hormone suppression may interact with the cholinergic system and the LIFG. We justified the ROI analysis at the LIFG on the findings of an earlier study using this paradigm (Craig et al., 2007b). However, given the importance of medial temporal cortex in memory encoding (Campo et al., 2005), and as a putative site of interaction between estradiol and M2 receptors in animal studies (Daniel et al., 2005), it was surprising that a further analysis confined to hippocampus did not detect an interaction . ...
... supporting the suggestion that LH may have a negative effect on cognition in aged transgenic mice). However, these findings are inconsistent with previous human studies (Craig et al., 2008aCraig et al., , 2007b Grigorova et al., 2006; Sherwin and Tulandi, 1996) which suggest that, in healthy young women, GnRHa (and reduced LH) is associated with reduced cognitive performance (i.e. the opposite to studies aged APP transgenic mice). Thus, although it is possible that LH may have an effect on cognition it is unlikely to explain the findings reported in this study. ...
Article
Women have an increased risk of developing Alzheimer's Dementia (AD) compared to men. It has been postulated that this risk may be modulated by a reduction in the neuroprotective effects of estrogen on the brain in the early postmenopausal period. This view is supported by, for example, findings that ovariectomy in younger women (i.e. prior to menopause) significantly increases the risk for the development of memory problems and AD in later life. However, the biological basis underlying these cognitive changes is still poorly understood. Our aim in the current study was to understand the interactive effects of acute, pharmacological-induced menopause (after Gonadotropin Hormone Releasing Hormone agonist (GnRHa) treatment) and scopolamine (a cholinergic antagonist used to model the memory decline associated with aging and AD) on brain functioning. To this end we used fMRI to study encoding during a Delayed Match to Sample (DMTS) (visual working memory) task. We report a relative attenuation in BOLD response brought about by scopolamine in regions that included bilateral prefrontal cortex and the left parahippocampal gyrus. Further, this was greater in women post-GnRHa than in women whose ovaries were functional. Our results also indicate that following pharmacological-induced menopause, cholinergic depletion produces a more significant behavioural deficit in overall memory performance, as manifest by increased response time. These findings suggest that acute loss of ovarian hormones exacerbate the effects of cholinergic depletion on a memory-related, behavioural measure, which is dependent on fronto-temporal brain regions. Overall, our findings point to a neural network by which acute loss of ovarian function may interact to negatively impact encoding.
... Each of these neurobiological differences between hormone therapy users and non-users was evident despite a lack of behavioral differences in performance, suggesting that neuroimaging techniques may detect effects of estrogen on the frontal lobes that are not yet apparent by behavioral measures. A series of neuroimaging investigations demonstrated a clear relationship between estradiol and activation in the frontal cortex during successful verbal encoding in healthy premenopausal women undergoing pharmacological ovarian hormone suppression with leuprolide acetate (Craig et al., 2007Craig et al., , 2008a, b). Hormone suppression led to decreased activation in left prefrontal cortex, anterior cingulate and medial frontal gyrus (Craig et al., 2007 ). ...
... A series of neuroimaging investigations demonstrated a clear relationship between estradiol and activation in the frontal cortex during successful verbal encoding in healthy premenopausal women undergoing pharmacological ovarian hormone suppression with leuprolide acetate (Craig et al., 2007Craig et al., , 2008a, b). Hormone suppression led to decreased activation in left prefrontal cortex, anterior cingulate and medial frontal gyrus (Craig et al., 2007 ). A subsequent investigation demonstrated that this effect was reversed when estradiol levels returned to normal, higher levels (Craig et al., 2008a ). ...
Article
Full-text available
Clinical trials yield discrepant information about the impact of hormone therapy on verbal memory and executive function. This issue is clinically relevant because declines in verbal memory are the earliest predictor of Alzheimer's disease and declines in executive function are central to some theories of normal, age-related changes in cognition. We conducted a systematic review of randomized clinical trials of hormone therapy (i.e. oral, transdermal, i.m.) and verbal memory, distinguishing studies in younger (i.e. <or=65 years of age; n = 9) versus older (i.e. >65 years; n = 7) women and studies involving estrogen alone versus estrogen plus progestogen. Out of 32 placebo-controlled trials, 17 were included (13 had no verbal memory measures and 2 involved cholinergic manipulations). We also provide a narrative review of 25 studies of executive function (two trials), since there are insufficient clinical trial data for systematic review. There is some evidence for a beneficial effect of estrogen alone on verbal memory in younger naturally post-menopausal women and more consistent evidence from small-n studies of surgically post-menopausal women. There is stronger evidence of a detrimental effect of conjugated equine estrogen plus medroxyprogesterone acetate on verbal memory in younger and older post-menopausal women. Observational studies and pharmacological models of menopause provide initial evidence of improvements in executive function with hormone therapy. Future studies should include measures of executive function and should address pressing clinical questions; including what formulation of combination hormone therapy is cognitively neutral/beneficial, yet effective in treating hot flashes in the early post-menopause.
... This observation is in line with studies showing that certain cognitive functions will decline with elevated GnRH, because chronic GnRH-treatment is expected to have the opposite effect of acute administration (Green et al., 2000). Using functional magnetic resonance imaging, Craig et al. (2007) reported that GnRHa-treatment over an 8-week period resulted in a reduction in verbal encoding (but not retrieval) that was associated with decreased hemodynamic activation in the left prefrontal cortex, anterior cingulate and medial frontal gyrus. Similarly, memory loss is a common side effect in men treated with GnRHa for metastatic prostate cancer (Flaig and Glode, 2008) and is associated with the decline in circulating concentrations of both androgens and estrogens (Salminen et al., 2004;Freedland et al., 2009). ...
Article
Full-text available
Chronic gonadotropin-releasing hormone agonist (GnRHa) treatment is effective for the medical suppression of the hypothalamic-pituitary-gonadal axis in situations like central precocious puberty and gender dysphoria. However, its administration during the peripubertal period could influence normal brain development and function because GnRH receptors are expressed in brain regions that regulate emotions, cognition, motivation and memory. This study used an ovine model to determine whether chronic peripubertal GnRHa-treatment affected the developmental shift from preference of familiarity to novelty. Experimental groups included Controls and GnRHa-treated rams. To differentiate between effects of altered GnRH signaling and those associated with the loss of sex steroids, a group was also included that received testosterone replacement as well as GnRHa (GnRHa + T). Preference for a novel versus familiar object was assessed during 5-min social isolation at 8, 28 and 46 weeks of age. Approach behavior was measured as interactions with and time spent near the objects, whereas avoidance behavior was measured by time spent in the entrance zone and attempts to escape the arena via the entry point. Emotional reactivity was measured by the number of vocalizations, escape attempts and urinations. As Control and GnRHa-treated rams aged, their approach behaviors showed a shift from preference for familiarity (8 weeks) to novelty (46 weeks). In contrast, relative to the Controls the GnRHa + T rams exhibited more approach behaviors towards both objects, at 28 and 46 weeks of age and preferred familiarity at 46 weeks of age. Vocalisation rate was increased in GnRHa treated rams in late puberty (28 weeks) compared to both Control and GnRHa + T rams but this effect was not seen in young adulthood (46 weeks). These results suggest that the specific suppression of testosterone during a developmental window in late puberty may reduce emotional reactivity and hamper learning a flexible adjustment to environmental change. The results also suggest that disruption of either endogenous testosterone signalling or a synergistic action between GnRH and testosterone signalling, may delay maturation of cognitive processes (e.g. information processing) that affects the motivation of rams to approach and avoid objects.
... Estrogen therapy increases frontal cortex activation and verbal recall, a process mediated by the prefrontal cortex, in peri-menopausal and post-menopausal women [241]. However, administration of a gonadotropinreleasing hormone agonist to pre-menopausal women decreases prefrontal activation and impairs verbal memory [242], revealing a nuanced role for estrogen action in the prefrontal cortex. ...
Article
Sex differences have been observed across many psychiatric diseases, especially mood disorders. For major depression, the most prevalent psychiatric disorder, females show a roughly two-fold greater risk as compared to males. Depression is sexually dimorphic with males and females exhibiting differences in clinical presentation, course, and response to antidepressant treatment. In this review, we first discuss sex differences observed in depressed patients, as well as animal models that reveal potential underlying mechanisms. We then discuss antidepressant treatments including their proposed mechanism of action and sex differences observed in treatment response. We include possible mechanisms underlying these sex differences with particular focus on synaptic transmission.
... In contrast, a neuroimaging approach focusing on brain regions subserving cognitive control has the potential to be sensitive enough to detect the effects of HT in the absence of behavioral change. Such experimental approach has previously proven useful to reveal estrogen effects on brain regions subserving verbal memory function, even in the absence of behavioral change [9][10][11][12] . ...
Article
Full-text available
Clinical data have been equivocal and controversial as to the benefits to the brain and cognition of hormone therapy (HT) in postmenopausal women. Recent reevaluation of the role of estrogens proposed that HT may effectively prevent the deleterious effects of aging on cognition, and reduces the risks of dementia, including Alzheimer’s disease, if initiated early at the beginning of menopause. Yet, little is known about the effects of HT on brain activation related to cognitive control, the ability to make flexible decisions in relation to internal goals. Here, we used fMRI to directly test for a modulation of sequential 17β estradiol (2 mg/day) plus oral progesterone (100 mg/day) on task switching-related brain activity in women at early postmenopause. The results showed that HT enhanced dorsolateral prefrontal cortex recruitment during task switching. Between-subjects correlation analyses revealed that women who engaged more the dorsolateral prefrontal cortex showed higher task switching performance after HT administration. These results suggest that HT, when taken early at the beginning of postmenopause, may have beneficial effect on cognitive control prefrontal mechanisms. Together, these findings demonstrate that HT can prevent the appearance of reduced prefrontal cortex activity, a neurophysiological measure observed both in healthy aging and early dementia.
... These findings are echoed by the growing number of neuroimaging studies that report menstrual cycle-dependent patterns of PFC activation in women, even in the absence of behavioral effects [13,[15][16][17][18]. A role for estrogens in the modulation of PFC function is also supported by findings of improved working memory in premenopausal women with higher levels of estradiol (E2) [19], postmenopausal women on hormonal therapy [20,21] and data showing that hormonal depletion in young women [22,23] and hormonal replacement in postmenopausal women [18,[24][25][26] modulate patterns of PFC activation. ...
Article
Inhibitory control is an important component of executive function. An emerging literature in humans suggests that inhibitory control is sexually dimorphic and modulated by sex steroids, but evidence for such a link in nonhuman animals is scarce. In this study, we examined the effects of menstrual cycle and biological sex on response inhibition, as measured by a Stop-Signal task, in the baboon (Papio papio). The monkeys (n=13) were socially-housed, with voluntary access to multiple touchscreen computerized stations. The task required monkeys to inhibit prepotent responses (touching a target, "Go" trials) following the appearance of a visual stop signal on 25% of the trials ("Stop" trials). The cognitive data, consisting of computerized records of the monkeys' performance on the Stop-Signal task over a year of testing, were matched to records of female sexual swellings. Same-day menstrual and cognitive data were available for 5 females, aged 5 to 18 years. These data were compared to those of 8 males (5-14 years old) performing the Stop-Signal task over the same time period. Contrary to our hypothesis, performance on the task was not significantly affected by the phase (ovulatory vs. luteal) of the cycle in females. However, males were slower than females on Go trials and were less efficient in inhibiting responses on Stop trials. Slower responses in males were indicative of a speed-accuracy trade-off, as overall accuracy was also better in males than in females. Analyses of trial history indicated that males did not speed as much as females following a successful Go trial, but did not differ from females in post-error slowing or post-inhibiting responses. Overall, the data show that biological sex modulates Stop-Signal performance in the baboon, with males exhibiting slower response execution overall, less efficient inhibition, but greater accuracy than females. This pattern of sex differences may reflect motivational sex differences in which males emphasize accuracy rather than speed. Interestingly, these sex differences do not seem to vary as a function of ovarian hormones in females. Males' greater focus on accuracy is possibly due to enhanced sensitivity to reward mediated by testosterone levels.
... Previous studies addressing the impact of hormonal contraceptives on neural activation reported heterogeneous results: Gingnell et al. (2013) observed lower reactivity in the left MFG and bilateral IFG in an emotion matching task in four week contraceptive user compared to non-users. The authors assumed that mood changes and involvement of MFG and IFG in social interaction processes were strongly affected by hormonal status (Craig et al., 2007). ...
Article
Androstadienone (ANDR), a bodily secreted steroid compound, is a socially relevant chemosignal that modulates subjective and (neuro)physiological responses, predominantly in females. The impact of ANDR on stress responses in males and females has not been explored. Therefore, this fMRI study aimed to examine psychosocial stress reactions induced by mental arithmetic and social evaluation on behavioral and hormonal levels (46 participants: 15 naturally cycling females in their early follicular phase (EF), 15 females on hormonal contraceptives (HC) and 16 males); and on a neural level (40 participants: 13 EF-females, 13 HC-females and 14 males) in an ANDR and placebo treatment repeated-measures design.
... These results are in line with two pharmacological intervention studies in premenopausal healthy women where hypogonadism after prolonged treatment with GnRHa did not affect visual and verbal memory performance or self-reported levels of perceived stress and depressive symptoms (Owens et al., 2002;Schmidt et al., 2013). Conversely, premenopausal women receiving longer-term GnRHa treatment (as preparation for surgery of benign uterine fibroids), show reduced activation in prefrontal regions during verbal encoding compared to controls (Craig et al., 2007), which supports alterations in the neural mechanisms underlying verbal memory with hypogonadism. In line with our findings, a study of 72 healthy pre-menopausal women, showed no association between longer-term hypogonadism and elevated self-reported mood-related symptoms; even in women who experienced severe nighttime hot flushes and disturbed sleep (Ben Dor et al., 2013). ...
Article
Background: Women show increased risk of depressive symptoms in life phases where ovarian steroid hormone levels fluctuate or decline rapidly. The risk mechanisms may include changes in mental state and affective cognition possibly mediated by serotonergic neurotransmission. Methods: In a randomized controlled double-blinded trial, 61 healthy women (mean age 24.3±4.9 years) were tested with measures of affective verbal memory, reaction time, mental distress, and serotonin transporter binding at baseline and at follow-up after receiving gonadotropin-releasing hormone agonist (GnRHa) or placebo intervention. Women also reported daily mood profiles during intervention. We tested direct effects of intervention and indirect effects through changes in serotonin transporter binding on verbal affective memory, simple reaction time and self-reported measures of mental distress, and further effects of GnRHa on daily mood. Results: GnRHa induced an increase in simple reaction time (p=0.03) and more pronounced fluctuations in daily self-reported mood in a manner dependent on baseline mood (p=0.003). Verbal affective memory recall, overall self-perceived mental distress, and serotonin transporter binding were not affected. Conclusions: In healthy women transient sex-steroid hormone fluctuations decrease speed of information processing and further produce more labile mood only in women with elevated levels of mood disturbances at baseline.
... Previous studies demonstrate the beneficial effects of estrogen therapy in older hypogonadal (post-menopausal) women on measures of verbal and visual memory in some (Kampen and Sherwin, 1994;Resnick et al., 1997;Joffe et al., 2006;Maki et al., 2001) but not all studies (Berman et al., 1997;Shaywitz et al., 1999;LeBlanc et al., 2001;Keenan et al., 2001). Additionally, several reports examined the effects of hypogonadism on cognitive performance in younger women receiving GnRH agonists for uterine fibroids or endometriosis (Sherwin and Tulandi, 1996;Grigorova et al., 2006), and in contrast to our data, the majority of these studies (Palomba et al., 2004;Craig et al., 2008a;Craig et al., 2008b;Craig et al., 2007;Varney et al., 1993) observed a significant decline in performance scores in measures of verbal memory, working memory, and visual recognition during hypogonadism compared with baseline. We were unable to identify significant declines in performance scores in tests of attention or verbal or visual memory during hypogonadism in this study. ...
Article
Background: Despite well-established sex differences in the performance on tests of several cognitive domains (e.g., visuospatial ability), few studies in humans have evaluated if these sex differences are evident both in the presence of circulating sex hormones and during sex steroid hormonal suppression. Sex differences identified in the relative absence of circulating levels of estradiol and testosterone suggest that differences in brain structure or function exist independent of current hormonal environment and are more likely a reflection of differing developmental exposures and/or genetic substrates. Objective: To evaluate cognitive performance in healthy eugonadal men and women before and again during GnRH agonist-induced hypogonadism. Methods: Men (n=16) and women (n=15) without medical or psychiatric illness were matched for IQ. Cognitive tests were performed at baseline (when eugonadal) and after 6-8 weeks of GnRH agonist-induced gonadal suppression. The test batteries included measures of verbal and spatial memory, spatial ability, verbal fluency, motor speed/dexterity, and attention/concentration. Data were analyzed using repeated-measures models. Results: During both eugonadism and hypogonadism, men performed significantly better than women on several measures of visuospatial performance including mental rotation, line orientation, Money Road Map, Porteus maze, and complex figure drawing. Although some test performances showed an effect of hormone treatment, the majority of these differences reflected an improved performance during hypogonadism compared with baseline (and probably reflected practice effects). Conclusion: The well-documented male advantage in visuospatial performance, which we observed during eugonadal conditions, was maintained in the context of short-term suppression of gonadal function in both men and women. These findings suggest that, in humans, sex differences in visuospatial performance are not merely dependent on differences in the current circulating sex steroid environment. Thus sex differences in visuospatial performance in adulthood could reflect early developmental effects of sex steroid exposure or other environmental exposures differing across the sexes as our data confirm that these differences are independent of circulating estradiol or testosterone levels in men and women.
... In a longitudinal study of women transitioning through the menopause indicated, perimenopausal women who used hormone therapy had improved verbal memory and increased activation in the left hippocampus during this memory task relatively to their counterparts who had never used hormone therapy (11). Further, experimental suppression of the reproductive axis in young women results in changes in verbal memory encoding which can be restored with restoration of ovarian function (44,45). Finally, prior work has shown more overnight physiologic hot flashes related to poorer verbal memory function (5). ...
Article
To test whether more physiologically assessed hot flashes were associated with more connectivity in the default mode network (DMN), the network of brain regions active during rest. We particularly focus on DMN networks supporting the hippocampus as this region is rich in estrogen (E) receptors (ER) and has previously been linked to hot flashes. Women underwent 24 hours of physiologic and diary hot flash monitoring, functional magnetic resonance imaging (MRI), 72 hours of sleep actigraphy monitoring, a blood draw, questionnaires, and physical measures. University medical center. Twenty midlife women aged 40-60 years who had their uterus and both ovaries and were not taking hormone therapy (HT). None. The DMN functional connectivity. Controlling for age, race, and education, more physiologically-monitored hot flashes were associated with greater DMN connectivity (beta, B [SE] = 0.004 [0.002]), particularly hippocampal DMN connectivity (B [SE] = 0.005 [0.002]). Findings were most pronounced for sleep physiologic hot flashes (with hippocampal DMN, B [SE] = 0.02 [0.007]). Associations also persisted controlling for sleep, depressive symptoms, and serum E2 concentrations. More physiologically-monitored hot flashes were associated with more DMN connectivity, particularly networks supporting the hippocampus. Findings were most pronounced for sleep hot flashes. Findings underscore the importance of continued investigation of the central nervous system in efforts to understand this classic menopausal phenomenon. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
... Berman and colleagues performed a seminal PET study using a GnRHa-induced hypogonadism model in 1997, and found higher blood flow in the inferior frontal gyrus during estrogen-or progestagen add-back to the GnRHa treatment (Berman et al., 1997). Three subsequent fMRI studies from Craig et al., though regionof-interest based, indicated a decreased activation of the same region, i.e., the left inferior frontal gyrus, during different memory tasks, after 8 weeks of pharmacological menopause (Craig et al., 2007b(Craig et al., , 2008a. Moreover, this effect was demonstrated to be reversible as reflected at re-examination six months after discontinuation of GnRHa treatment (Craig et al., 2008b). ...
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The level of gonadal hormones to which the female brain is exposed considerably changes across the menopausal transition, which in turn, is likely to be of great relevance for neurodegenerative diseases and psychiatric disorders. However, the neurobiological consequences of these hormone fluctuations and of hormone replacement therapy in the menopause have only begun to be understood. The present review summarizes the findings of thirty-five studies of human brain function, including functional magnetic resonance imaging, positron and single-photon computed emission tomography studies, in peri- and postmenopausal women treated with estrogen, or estrogen-progestagen replacement therapy. Seven studies using gonadotropin-releasing hormone agonist intervention as a model of hormonal withdrawal are also included. Cognitive paradigms are employed by the majority of studies evaluating the effect of unopposed estrogen or estrogen-progestagen treatment on peri- and postmenopausal women's brain. In randomized-controlled trials, estrogen treatment enhances activation of fronto-cingulate regions during cognitive functioning, though in many cases no difference in cognitive performance was present. Progestagens seems to counteract the effects of estrogens. Findings on cognitive functioning during acute ovarian hormone withdrawal suggest a decrease in activation of the left inferior frontal gyrus, thus essentially corroborating the findings in postmenopausal women. Studies of the cholinergic and serotonergic systems indicate these systems as biological mediators of hormonal influences on the brain. More, hormonal replacement appears to increase cerebral blood flow in several cortical regions. On the other hand, studies on emotion processing in postmenopausal women are lacking. These results call for well-powered randomized-controlled multi-modal prospective neuroimaging studies as well as investigation on the related molecular mechanisms of effects of menopausal hormonal variations on the brain.
... 4 Conversely, suppression of gonadal steroid hormones decreases brain activation in the prefrontal cortex. 5 As individuals age, regardless of sex, the ability to remember words gradually declines, even in the absence of any dementing process. This decline is the troubling manifestation of the natural history of brains growing older. ...
... Evidence for this assumption may be drawn from a study on young women treated with gonadotropin releasing hormone agonists, which resulted in suppressed estradiol levels. Following eight weeks of treatment, the estradiol suppression obtained was associated with impaired verbal memory performance (Craig et al., 2007). ...
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The menstrual cycle has attracted research interest ever since the 1930s. For many researchers the menstrual cycle is an excellent model of ovarian steroid influence on emotion, behavior, and cognition. Over the past years methodological improvements in menstrual cycle studies have been noted, and this review summarizes the findings of methodologically sound menstrual cycle studies in healthy women. Whereas the predominant hypotheses of the cognitive field state that sexually dimorphic cognitive skills that favor men are improved during menstrual cycle phases with low estrogen and that cognitive skills that favor women are improved during cycle phases with increased estrogen and/or progesterone, this review has not found sufficient evidence to support any of these hypotheses. Mental rotation has gained specific interest in this aspect, but a meta-analysis yielded a standardized mean difference in error rate of 1.61 (95% CI −0.35 to 3.57), suggesting, at present, no favor of an early follicular phase improvement in mental rotation performance. Besides the sexually dimorphic cognitive skills, studies exploring menstrual cycle effects on tasks that probe prefrontal cortex function, for instance verbal or spatial working memory, have also been reviewed. While studies thus far are few, results at hand suggest improved performance at times of high estradiol levels. Menstrual cycle studies on emotional processing, on the other hand, tap into the emotional disorders of the luteal phase, and may be of relevance for women with premenstrual disorders. Although evidence at present is limited, it is suggested that emotion recognition, consolidation of emotional memories, and fear extinction is modulated by the menstrual cycle in women. With the use of functional magnetic resonance imaging, several studies report changes in brain reactivity across the menstrual cycle, most notably increased amygdala reactivity in the luteal phase. Thus, to the extent that behavioral changes have been demonstrated over the course of the menstrual cycle, the best evidence suggests that differences in sexually dimorphic tasks are small and difficult to replicate. However, emotion-related changes are more consistently found, and are better associated with progesterone than with estradiol such that high progesterone levels are associated with increased amygdala reactivity and increased emotional memory.
... Together these neuroimaging findings are notable in light of data from older female monkeys treated with cyclic estradiol where treatment was associated with enhanced formation of spines in the prefrontal cortex 78 and enhanced performance on tasks mediated by prefrontal cortex and medial temporal lobe 76 . Studies of pharmacological suppression of ovarian hormones with the gonadotropin-releasing hormone (GnRH) agonist analog, leuprolide acetate, provide evidence that loss of estrogen impairs memory and prefrontal function and that add-back estrogen reverses those effects 93,94 . Additionally, some studies have found that the volume of the hippocampus is larger in women who use HT [95][96][97] and varies depending on the timing of HT such that the shorter the delay in treatment between menopause and initiation of treatment, the greater the volume. ...
Article
Objective: The critical window hypothesis of hormone therapy (HT) and cognitive function states that the effects of HT depend on timing of initiation with respect to age, the menopausal transition, or both, and that optimal effects are evident with early initiation. This article reviews clinical studies that bear on this hypothesis. Methods: Recognizing that the typical pattern of HT use is early HT initiation, this review describes findings from observational studies of ever use of HT and observational studies that looked specifically at the timing of HT on Alzheimer's disease (AD) and cognitive test performance. Randomized trials of HT and verbal memory are discussed, and neuroimaging studies bearing on the hypothesis are reviewed. Results: Observational data suggest that HT generally reduces the risk of AD. Three of three observational studies that specifically examined the timing of initiation in relation to AD risk each provide support for the window, whereas three of five observational studies of HT timing and cognitive test performance do. Randomized clinical trials of estrogen therapy in younger women find support for the hypothesis. Conjugated equine estrogens/medroxyprogesterone acetate increases risks regardless of timing. Little is known about the cognitive effects of other combination HT formulations. Conclusions: A definitive trial to test the critical window hypothesis is not feasible. Evidence drawn from other sources provides initial support for the hypothesis. Although these findings are relevant to women who use HT to treat vasomotor symptoms, HT is currently not indicated for the treatment of cognitive complaints or for dementia prevention.
... A number of animal and clinical studies support a nonreproductive role for GnRH-I. Although the direct effect of GnRH-I on the neuronal networks that regulate behaviour is still poorly understood, it has been suggested that GnRH-I may also have effects on learning and memory (30,31) and anxiety (32,33). ...
Article
Gonadotrophin-releasing hormone (GnRH) was first isolated in the mammal and shown to be the primary regulator of the reproductive system through its initiation of pituitary gonadotrophin release. Subsequent to its discovery, this form of GnRH has been shown to be one of many structural variants found in the brain and peripheral tissues. Accordingly, the original form first discovered and cloned in the mammal is commonly referred to as GnRH-I. In addition to the complex regulation of GnRH-I synthesis, release and function, further evidence suggests that the processing of GnRH-I produces yet another layer of complexity in its activity. GnRH-I is processed by a zinc metalloendopeptidase EC 3.4.24.15 (EP24.15), which cleaves the hormone at the covalent bond between the fifth and sixth residue of the decapeptide (Tyr(5)-Gly(6)) to form GnRH-(1-5). It was previously thought that the cleavage of GnRH-I by EP24.15 represents the initiation of its degradation. Here, we review the evidence for the involvement of GnRH-(1-5), the metabolite of GnRH-I, in the regulation of GnRH-I synthesis, secretion and facilitation of reproductive behaviour.
Article
Objective Determine associations of endogenous estrogens with memory systems in the postmenopausal brain and evaluate clinical significance. Study Design In the MsBrain cohort (n=199, mean age 59.3+3.9 years, 83.9% white), we examined the cross-sectional association of serum estradiol and estrone, measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS), during a functional magnetic resonance imaging (fMRI) task of word encoding and recognition. To characterize the clinical significance of those associations, we examined the magnitude of activation in relation to a neuropsychological measures of memory and affect. Results Endogenous estradiol was positively associated with activation in temporal and frontal cortices during encoding and negatively associated with one prefrontal region during recognition (p<.05). Activation in the left inferior frontal gyrus was associated with memory performance (β(SE)= 0.004(0.002), p<.05), and anxiety (β(SE)= -0.100(0.050), p<.05). The left middle frontal gyrus was associated with memory performance (β(SE)= 0.006(0.002), p<.01), depression, and anxiety. The left superior temporal gyrus (STG) was associated with depression (β(SE)= -0.083(0.036), p<.05) and anxiety (β(SE)= -0.134(0.058), p<.05). Estrone was positively associated with activation in a range of brain areas including bilateral STG and right superior frontal gyrus during encoding (p<.05). Activation of the left insula an precental gyrus were associated with symptoms of depression and anxiety. None related to memory. Conclusion The function of brain areas critical to memory performance varies with estrogen levels in the postmenopause, even though those levels are low. Higher levels of estradiol may facilitate memory performance through enhanced function of temporal and frontal cortices during encoding of verbal material.
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Background A human perception-based assessment of multi-parametric magnetic resonance imaging (mpMRI) of the prostate does not necessarily tap the full potential in determining prostate cancer (PCa) and identifying significant prostate cancer (sPCa). Methods Our multi-institutional international study includes 6,448 mpMRI prostate images from 1,830 patients (PCa diagnosis in 69.7% of patients). MR Images from a single institution were utilized for the model development and in-house validation, and from two international institutions for external validation. We utilized volumetric data, PlexusNET architecture, and attention algorithms to develop deep learning models. Performance was measured using the area under receiving characteristic operating curve (AUROC) and compared to the PI-RADS score system (version 2) at the case level for PCa diagnosis and sPCa identification. The reduction rate of biopsy settings without missing any PCa cases measured the clinical utility. Results Our compact models were internally and externally validated for a significant improvement in PCa detection by 7.25% compared to the PI-RADS score system. Following the model recommendation would avoid at least 11.3% of unnecessary biopsies. Moreover, the DL model correctly predicted PCa presence in 22.5% of cases, which were misclassified according to the PI-RADS score system. The identification accuracy of sPCa for the model was statistically significantly higher than PI-RADS scores (AUROC: 0.769 vs. 0.726; p < 0.021) on a PCa cohort with 79% sPCa. Conclusions Our solution facilitates mpMRI assessment of the prostate for PCa diagnosis and the determination of sPCa; we demonstrated a great potential of AI for clinical utility and improved mpMRI assessment.
Chapter
The human brain continues to develop and change throughout life. Structural and functional studies research helps us to understand that the brain matures through gestation, infancy, childhood, adolescence and into young adulthood up until the mid to late twenties (Kolb and Whishaw, 2015). Healthy brain maturation during childhood and adolescence supports learning through these years and is considered essential for normative cognitive, social, and emotional development, setting the scene for a healthy, positive adulthood. Puberty is a key stage in development involving a complex cascade of hormonal changes, particularly those identified as sex hormones (androgens and estrogens) and the hypothalamic and pituitary hormones that control their release. Although most often researched in relation to puberty, the effect of sex hormones on our bodies and brains begins in utero and continue throughout our life. Despite the clear overlap in timing of brain development and the fluctuation of hormones throughout the first 20 years of our life, research investigating the association between the two from a developmental point of view is much less well developed than might be expected. This chapter will provide a brief review of brain development including in utero maturation through to adolescence and discuss the simultaneously occurring sex hormone changes occurring throughout this period. Following this, we present a review and critique of the literature investigating the role of sex hormones on brain development and functioning across both animal and human studies and examine how this links with adolescent brain development and the associated changes in neurocognitive functioning. Finally, we use provided case study that illustrates the potential relevance of these findings to modern clinical practice.
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Silver-Russell syndrome (SRS) is a rare genetic disorder (estimated incidence 1/30,000 to 100,000 live births). So far, only a few studies have focused on the cognitive profile of individuals with SRS, and these were conducted some time ago, concentrated on pediatric cohorts, and included patients who had been diagnosed using a variety of clinical diagnostic systems. There has yet to be any research on the intellectual functioning of adults with SRS. This study sought to establish the intelligence, strengths and weaknesses within intellectual profile of adults with SRS, compared with normative data. Ten individuals with 11p15 epimutation aged 18–39 years completed the Wechsler Adult Intelligence Scale-Fourth Edition. Measures of interest included participants’ intelligence (Full Scale Intelligence Quotient [FSIQ]) and four domains of cognitive functioning: verbal comprehension, perceptual reasoning, working memory and processing speed. Discrepancy scores were calculated, and descriptive statistical and linear correlations were used to investigate factors associated with IQ outcome. Clinical and medical information such as rehabilitation, and perceived difficulties in daily life were collected by interviews and questionnaires. Results showed that the mean FSIQ score was in the average range (M = 95.40, SD = 18.55) and they performed best on verbal comprehension. Frequent daily difficulties were reported by patients and/or their families: learning disabilities and low self-esteem were perceived by 60% of adults. Early intervention and multidisciplinary care from childhood to adulthood are important in SRS for care potential medical, cognitive and psychosocial problems. This is the first study to document the intellectual functioning of adults with SRS.
Chapter
Since the Women's Health Initiative report of 2002, there has been reluctance to provide women with hormone replacement therapy due to a lack of clarity about the potential risks. This book reviews all aspects of the menopause and places the benefits and risks of hormone therapy into perspective. It fully informs the reader regarding the evidence base of all aspects of menopause medicine and can be used either as a reference book to solve specific problems, or as a book to be read cover-to-cover. It will provide the reader with the latest information and as a result encourage confidence in managing menopause related problems. This practical, evidence-based guide is suitable for all health professionals managing the menopause including gynaecologists, sexual and reproductive medicine specialists, general practitioners and trainees in any of the above specialties.
Chapter
Since the Women's Health Initiative report of 2002, there has been reluctance to provide women with hormone replacement therapy due to a lack of clarity about the potential risks. This book reviews all aspects of the menopause and places the benefits and risks of hormone therapy into perspective. It fully informs the reader regarding the evidence base of all aspects of menopause medicine and can be used either as a reference book to solve specific problems, or as a book to be read cover-to-cover. It will provide the reader with the latest information and as a result encourage confidence in managing menopause related problems. This practical, evidence-based guide is suitable for all health professionals managing the menopause including gynaecologists, sexual and reproductive medicine specialists, general practitioners and trainees in any of the above specialties.
Chapter
From a psychological perspective, the menstrual cycle has been a research topic for more than 50 years. The most recent menstrual cycle research has been driven by an increased interest in sex differences in neuroscience, and the urge to understand sex disparities in prevalence, clinical presentation, and treatment response in psychiatric or neurologic disorders. Indeed, the menstrual cycle is an excellent model of ovarian steroid influence on emotion, behavior, and cognition.This review summarizes the emotion-related and cognitive findings of methodologically sound menstrual cycle studies. In particular, the review is devoted to the sex hormone-induced emotional disturbances in women with premenstrual dysphoric disorder, a subgroup of women responding with enhanced sensitivity to the normal fluctuations in endogenous hormone levels during the menstrual cycle. In addition, emotion processing and cognitive findings across the menstrual cycle in healthy women are also discussed.The overall conclusion is that that menstrual cycle differences in sexually dimorphic cognitive tasks are small and difficult to replicate. Emotion-related changes are more consistently found and are better associated with progesterone and the luteal phase, than with estradiol.
Chapter
Introduction The history and management of the menopause has, for thousands of years, been bound up in the mystique surrounding the presence or absence of the regular loss of vaginal blood from a woman [1, 2]. Early accounts that mentioned the role of menstruation appear to suggest that the regular loss of blood was regarded as nature's mechanism to purge the female body of foul and poisonous fluids. As a result, menstrual blood was regarded as being unclean, revolting and toxic, and to be avoided whenever possible. This fear of menstrual blood influenced and dictated the social and political role that women were allocated in a community and eventually resulted in many unnecessary and cruel treatments [1]. Equally, the absence of regular menstruation with a resultant failure to rid the body of toxins was regarded as the reason some women went “mad” or developed antisocial behavior. From the pre-Christian era to the 19th century, knowledge about a woman's menstrual activity and its causes was dominated by a male perception of how it came about, what was its purpose and what happened when a woman stopped menstruating. Early Greek and Roman physicians felt that menstrual blood was necessary to rid the female body of “bad humors” and that the symptoms of the menopause came about because the accumulated toxins in the menstrual blood were not being released. The symptoms of menopause – episodes of heat, emotional mood swings, depression, sexual dysfunction and even osteoporotic fractures have been mentioned in early texts by the ancient Hippocratic and the Aristotle schools of health and hygiene, both of which postulated that as a woman aged, she was no longer capable of producing the nourishment necessary to form menstrual blood [1, 2]. For that reason these physicians prescribed special diets including spices, fungi and herbs to treat those women who suffered from psychological and vasomotor symptoms.
Chapter
Since the Women's Health Initiative report of 2002, there has been reluctance to provide women with hormone replacement therapy due to a lack of clarity about the potential risks. This book reviews all aspects of the menopause and places the benefits and risks of hormone therapy into perspective. It fully informs the reader regarding the evidence base of all aspects of menopause medicine and can be used either as a reference book to solve specific problems, or as a book to be read cover-to-cover. It will provide the reader with the latest information and as a result encourage confidence in managing menopause related problems. This practical, evidence-based guide is suitable for all health professionals managing the menopause including gynaecologists, sexual and reproductive medicine specialists, general practitioners and trainees in any of the above specialties.
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Iatrogenic hyperprolactinaemia (IHPRL) has been more frequently related to some antipsychotic drugs that provoke an intense blockade of dopamine D2 receptors. There is a wide variation in clinical practice, and perhaps some more awareness between clinicians is needed. Due to the high frequency of chronic treatment in severe mental patients, careful attention is recommended on the physical risk. IHPRL symptoms could be underestimated without routine examination.
Article
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Central precocious puberty (CPP) develops due to premature activation of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in early pubertal changes and rapid bone maturation. CPP is associated with lower adult height and increased risk for development of psychological problems. Standard treatment of CPP is based on postponement of pubertal development by blockade of the HPG axis with gonadotropin releasing hormone analogs (GnRHa) leading to abolition of gonadal sex hormones synthesis. Whereas the hormonal and auxological effects of GnRHa are well-researched, there is a lack of knowledge whether GnRHa treatment influences psychological functioning of treated children, despite the fact that prevention of psychological problems is used as one of the main reasons for treatment initiation. In the present study we seek to address this issue by exploring differences in cognitive function, behavior, emotional reactivity, and psychosocial problems between GnRHa treated CPP girls and age-matched controls. Fifteen girls with idiopathic CPP; median age 10.4 years, treated with slow-release GnRHa (triptorelin acetate—Decapeptyl SR® 11.25) and 15 age-matched controls, were assessed with a comprehensive test battery consisting of paper and pencil tests, computerized tasks, behavioral paradigms, heart rate variability, and questionnaires filled in by the children's parents. Both groups showed very similar scores with regard to cognitive performance, behavioral and psychosocial problems. Compared to controls, treated girls displayed significantly higher emotional reactivity (p = 0.016; Cohen's d = 1.04) on one of the two emotional reactivity task conditions. Unexpectedly, the CPP group showed significantly lower resting heart rates than the controls (p = 0.004; Cohen's d = 1.03); lower heart rate was associated with longer treatment duration (r = −0.582, p = 0.037). The results suggest that GnRHa treated CPP girls do not differ in their cognitive or psychosocial functioning from age matched controls. However, they might process emotional stimuli differently. The unexpected finding of lower heart rate that was associated with longer duration of the treatment should be further explored by methods appropriate for assessment of cardiac health.
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Introduction: Iatrogenic hyperprolactinaemia (IHPRL) has been more frequently related to some antipsychotic drugs that provoke an intense blockade of dopamine D2 receptors. There is a wide variation in clinical practice, and perhaps some more awareness between clinicians is needed. Due to the high frequency of chronic treatment in severe mental patients, careful attention is recommended on the physical risk. IHPRL symptoms could be underestimated without routine examination. Methodology: An intense scientific literature search was performed in order to draw up a multidisciplinary consensus, including different specialists of psychiatry, endocrinology, oncology and internal medicine, and looking for a consensus about clinical risk and detection of IHPRL following evidence-based medicine criteria levels (EBM I- IV). Results: Short-term symptoms include amenorrhea, galactorrhoea, and sexual dysfunction with decrease of libido and erectile difficulties related to hypogonadism. Medium and long-term symptoms related to oestrogens are observed, including a decrease bone mass density, hypogonadism, early menopause, some types of cancer risk increase (breast and endometrial), cardiovascular risk increase, immune system disorders, lipids, and cognitive dysfunction. Prolactin level, gonadal hormones and vitamin D should be checked in all patients receiving antipsychotics at baseline although early symptoms (amenorrhea-galactorrhoea) may not be observed due to the risk of underestimating other delayed symptoms that may appear in the medium term. Routine examination of sexual dysfunction is recommended due to possible poor patient tolerance and low compliance. Special care is required in children and adolescents, as well as patients with PRL levels >50ng/ml (moderate hyperprolactinaemia). A possible prolactinoma should be investigated in patients with PRL levels >150ng/ml, with special attention to patients with breast/endometrial cancer history. Densitometry should be prescribed for males >50 years old, amenorrhea>6 months, or early menopause to avoid fracture risk.
Chapter
Since the Women's Health Initiative report of 2002, there has been reluctance to provide women with hormone replacement therapy due to a lack of clarity about the potential risks. This book reviews all aspects of the menopause and places the benefits and risks of hormone therapy into perspective. It fully informs the reader regarding the evidence base of all aspects of menopause medicine and can be used either as a reference book to solve specific problems, or as a book to be read cover-to-cover. It will provide the reader with the latest information and as a result encourage confidence in managing menopause related problems. This practical, evidence-based guide is suitable for all health professionals managing the menopause including gynaecologists, sexual and reproductive medicine specialists, general practitioners and trainees in any of the above specialties.
Chapter
Since the Women's Health Initiative report of 2002, there has been reluctance to provide women with hormone replacement therapy due to a lack of clarity about the potential risks. This book reviews all aspects of the menopause and places the benefits and risks of hormone therapy into perspective. It fully informs the reader regarding the evidence base of all aspects of menopause medicine and can be used either as a reference book to solve specific problems, or as a book to be read cover-to-cover. It will provide the reader with the latest information and as a result encourage confidence in managing menopause related problems. This practical, evidence-based guide is suitable for all health professionals managing the menopause including gynaecologists, sexual and reproductive medicine specialists, general practitioners and trainees in any of the above specialties.
Chapter
This chapter discusses the beneficial mental health effects of soy and soy products in older women. Soy products contain phytoestrogens, which are naturally occurring estrogen compounds and with concerns of risks of hormone therapy to women's health, has led to an increase in use of soy supplements for menopausal symptoms. It mentions that estrogen benefit memory and cognition in younger postmenopausal women, suggesting the potential of soy to enhance cognition in older women. Soy and soy products are one of the richest sources of bioactive antioxidants known as isoflavones, which act as both an antioxidant and as phytoestrogen. A brief account of the cognition enhancing effect of estrogen and soy in women is given. In animal studies, the effect of soy is indicated to be sex-specific, being beneficial for females but not males. It concludes that the mental health effects of soy appear to confer cognitive benefits in young women and early postmenopausal women. However, there is not enough evidence to support the use of phytoestrogens as cognition enhancers in late menopausal women.
Article
Premature ovarian insufficiency (POI) involves loss of ovarian function before age 40. POI has been associated with neurological dysfunction and an increased risk of dementia, perhaps due to depletion in estrogen levels. The present review discusses the effects of POI caused by genetic disorder, natural premature menopause, surgical menopause, breast cancer treatment and gonadotropin-releasing hormone (GnRH) agonist treatment. Overall, data suggest an increased risk of neurological disorder where POI is due to premature menopause or induced from surgery. This increased risk appears to be most apparent on domains of global cognitive and verbal memory tests. Where POI is caused by genetic disorder, observed cognitive deficiencies may be more likely to have a genetic basis rather than being due to the effects of sex steroids on the brain. Findings related to loss of cognitive function after chemotherapy or GnRH treatments are mixed. There are also discrepant data related to use of hormone therapy after POI (particularly after surgical menopause). After surgery, hormone treatment appears to be most beneficial if initiated close to the average natural age of menopause.
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The prevailing assumption by some that deep processing promotes stronger learning outcomes while surface processing promotes weaker learning outcomes has been called into question by the inconsistency and ambiguity of results in investigations of the relation between levels of processing and performance. The purpose of this literature review is to examine four areas that may be contributing to the inconsistency and ambiguity of these research results: conceptualization, operationalization, situational factors, and model specification of deep and surface processing. A PsycINFO database search was conducted, and 221 studies were identified for a comprehensive data table. Analysis of these data revealed trends that suggested conceptualization and operationalization of deep and surface processing differed depending on the theoretical frame utilized in each study. Additionally, the choice of theoretical frame also seemed to impact what situational factors may or may not have been present as well as how the model of levels of processing and performance was specified. Results from studies that met certain criteria demonstrated that levels of processing and performance are related, and further, these relations may be moderated by other factors. Implications for future research are discussed that focus on these four areas.
Article
Objective: Most women on combined oral contraceptives (COC) report high levels of satisfaction, but 4-10% complain of adverse mood effects. The aim of this randomized, double-blinded, placebo-controlled trial was to investigate if COC use would induce more pronounced mood symptoms than placebo in women with previous history of COC-induced adverse mood. A second aim was to determine if COC use is associated with changes in brain reactivity in regions previously associated with emotion processing. Methods: Thirty-four women with previous experience of mood deterioration during COC use were randomized to one treatment cycle with a levonorgestrel-containing COC or placebo. An emotional face matching task (vs. geometrical shapes) was administered during functional magnetic resonance imaging (fMRI) prior to and during the COC treatment cycle. Throughout the trial, women recorded daily symptom ratings on the Cyclicity Diagnoser (CD) scale. Results: During the last week of the treatment cycle COC users had higher scores of depressed mood, mood swings, and fatigue than placebo users. COC users also had lower emotion-induced reactivity in the left insula, left middle frontal gyrus, and bilateral inferior frontal gyri as compared to placebo users. In comparison with their pretreatment cycle, the COC group had decreased emotion-induced reactivity in the bilateral inferior frontal gyri, whereas placebo users had decreased reactivity in the right amygdala. Conclusion: COC use in women who previously had experienced emotional side effects resulted in mood deterioration, and COC use was also accompanied by changes in emotional brain reactivity. These findings are of relevance for the understanding of how combined oral contraceptives may influence mood. Placebo-controlled fMRI studies in COC sensitive women could be of relevance for future testing of adverse mood effects in new oral contraceptives.
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To prospectively examine alterations in working memory (WM) -associated brain activation related to breast cancer and treatment by using functional magnetic resonance imaging. Patients treated with chemotherapy (CTx+; n = 16) or without chemotherapy (CTx-; n = 12) and healthy controls (n = 15) were scanned during an n-back task at baseline (after surgery but before radiation, chemotherapy, and/or antiestrogen treatment), 1 month after completion of chemotherapy (M1), and 1 year later (Y1), or at yoked intervals for CTx- and controls. SPM5 was used for all image analyses, which included cross-sectional between-group and group-by-time interaction and longitudinal within-group analyses, all using a statistical threshold of 0.001. At baseline, patients with cancer showed increased bifrontal and decreased left parietal activation compared with controls. At M1, both cancer groups showed decreased frontal hyperactivation compared with controls, with increased hyperactivation at Y1. These cross-sectional findings were confirmed by group-by-time interaction analyses, which showed frontal activation decreases from baseline to M1 in patients compared with controls. Within-group analyses showed different patterns of longitudinal activation change by treatment group (CTx+ or CTx-), with prominent alterations in the frontal lobes bilaterally. Significant frontal lobe hyperactivation to support WM was found in patients with breast cancer. Superimposed on this background, patients showed decreased frontal activation at M1, with partial return to the previously abnormal baseline at Y1. These functional changes correspond to frontal lobe regions where we previously reported structural changes in this cohort and provide prospective, longitudinal data that further elucidate mechanisms underlying cognitive effects related to breast cancer and its treatment.
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The focus of this chapter is the relationship between the onset of depression in women and the reproductive events of the menopause transition. Epidemiologic studies have documented that the majority of women do not become depressed during the menopause transition. However, recent longitudinal studies suggest that in some women, the reproductive events related to the menopause transition could play a role in the onset of depression. No abnormality of ovarian hormones has been identified that distinguishes women with depression from those who remain asymptomatic during the menopause transition. Nonetheless, several findings suggest a role of ovarian hormones in the onset of these depressions. First, episodes of depression cluster during the stage of the menopause transition that is accompanied by estradiol withdrawal. Second, randomized controlled trials have documented the short-term (3-6 weeks) antidepressant efficacy of estradiol in depressed perimenopausal women. Third, experimentally induced estradiol withdrawal triggers mood symptoms in some women. Thus, although depression is not a uniform accompaniment of the menopause transition, in some women, age-related changes in ovarian estrogen production may alter central nervous system function and predispose them to develop depression.
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We describe almost entirely automated procedures for estimation of global, voxel, and cluster-level statistics to test the null hypothesis of zero neuroanatomical difference between two groups of structural magnetic resonance imaging (MRI) data. Theoretical distributions under the null hypothesis are available for 1) global tissue class volumes; 2) standardized linear model [analysis of variance (ANOVA and ANCOVA)] coefficients estimated at each voxel; and 3) an area of spatially connected clusters generated by applying an arbitrary threshold to a two-dimensional (2-D) map of normal statistics at voxel level. We describe novel methods for economically ascertaining probability distributions under the null hypothesis, with fewer assumptions, by permutation of the observed data. Nominal Type I error control by permutation testing is generally excellent; whereas theoretical distributions may be over conservative. Permutation has the additional advantage that it can be used to test any statistic of interest, such as the sum of suprathreshold voxel statistics in a cluster (or cluster mass), regardless of its theoretical tractability under the null hypothesis. These issues are illustrated by application to MRI data acquired from 18 adolescents with hyperkinetic disorder and 16 control subjects matched for age and gender.
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This study examined the effects of hormone-replacement therapy on memory and other cognitive abilities in cognitively intact older women. This prospective observational study in nondemented postmenopausal women aged 50-89 from the Baltimore Longitudinal Study of Aging involved study groups consisting of 103 women who were receiving oral or transdermal estrogen-replacement therapy (44 of whom were receiving adjuvant progesterone) and 81 women who had never received such therapy. Groups were naturally matched on education, health status, depressive symptoms, annual income, and general verbal ability. To restrict the study group to cognitively healthy women, prospective clinical data were used to exclude women who developed dementia up to 5 years after assessment. Data were cross-sectional. Multivariate analysis of variance and follow-up univariate analyses of variance were performed to compare those women who were receiving and those who had never received hormone-replacement therapy on measures of verbal memory, figural memory, mental rotations, attention, and working memory. The women receiving hormone-replacement therapy performed significantly better on measures of verbal learning and memory than did those who had never received hormones, but there were no significant differences in scores on other cognitive tests. Specific aspects of memory performance, including encoding and retrieval, were superior among the women receiving hormone therapy. These findings, based on groups of women who were receiving and had never received hormone-replacement therapy and who were naturally matched on health and cognitive status, suggest that hormone-replacement therapy may have a selective beneficial effect on verbal memory in older nondemented women.
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To examine alterations in brain activation associated with pharmacologically induced memory impairment, we used functional MRI (fMRI) to study the effects of lorazepam and scopolamine on a face-name associative encoding paradigm. Ten healthy young subjects were scanned on four occasions, 2 weeks apart; they were administered i.v. saline during two placebo-scanning sessions and then alternately administered i.v. lorazepam (1 mg) or scopolamine (0.4 mg) in a double-blind, randomized, cross-over design. Both the extent and magnitude of activation within anatomic regions of interest (ROIs) were examined to determine the reproducibility of activation in the placebo sessions and the regional specificity of the pharmacologic effects. Activation within all ROIs was consistent across the two placebo scans during the encoding of novel face-name pairs (compared with visual fixation). With the administration of either lorazepam or scopolamine, significant decreases were observed in both the extent and magnitude of activation within the hippocampal, fusiform, and inferior prefrontal ROIs, but no significant alterations in activation in the striate cortex were found. Both medications impaired performance on postscan memory measures, and significant correlations between memory performance and extent of activation were found in hippocampal and fusiform ROIs. These findings suggest that pharmacologic effects can be detected with fMRI by using a reproducible experimental paradigm and that medications that impair memory also diminish activation in specific brain regions thought to subserve complex memory processes.
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Treatment of women with uterine myomas with GnRH agonists results in symptoms of hypoestrogenism which can be prevented by concurrent "add-back" estrogen administration. We took advantage of these induced endocrine changes to investigate their effects on cognitive functioning in young women with myomas. Nineteen women with uterine myomas were tested before treatment. They all received the GnRH agonist, leuprolide acetate depot (LAD), every 4 weeks for 12 weeks and were then randomized to receive LAD plus estrogen or LAD plus placebo every 4 weeks for 8 additional weeks. Levels of all sex hormones decreased after 12 weeks of LAD treatment (P < 0.01), and only estradiol (E2) levels increased (P < 0.01) following 8 weeks of subsequent treatment in the group that received LAD plus E2. Scores on neuropsychological tests of verbal memory decreased from pretreatment to 12 weeks posttreatment with LAD (P < 0.05). These memory deficits were reversed in the group that received LAD plus E2 for 8 weeks coincident with an increase in plasma E2, whereas memory scores remained depressed in the group that received LAD plus placebo. These findings are consistent with those from studies on surgically menopausal women and strongly suggest that estrogen serves to maintain verbal memory in women. These results provide support for the efficacy of add-back estrogen regimens in women treated with GnRH agonists and also imply that estrogen may be important for maintaining memory in the postmenopause.
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Objective To compare the efficacy and safety of goserelin depot and danazol for endometriosis. Design Open, randomized comparative trial. Setting Multicenter European academic clinical institutions. Patients A total of 307 patients with laparoscopically diagnosed endometriosis were randomized to goserelin (n = 204) or danazol (n = 103); 249 patients underwent second look laparoscopy (175 received goserelin and 74 danazol) and were analyzed for efficacy. Interventions A 3.6-mg depot of goserelin monthly subcutaneously or oral danazol 200 mg three times a day administered for 24 weeks. Main Outcome Measures Efficacy assessments were based on changes in visible deposits at laparoscopy before and after treatment and subjective symptom scores at 4-week intervals during treatment and 8-week intervals after treatment for up to 24 weeks. Safety was assessed by adverse event reporting and clinical laboratory measures. Results There were similar proportions of symptomatic (73%) and asymptomatic (but infertile) (27%) and comparable distribution of different severity of endometriosis randomized to each treatment. Significantly fewer patients randomized to goserelin (6.4%) withdrew during treatment compared with 20.4% randomized to danazol ( P P P Conclusions The monthly administered 3.6-mg depot preparation of goserelin was highly effective at inducing resolution of endometriotic implants and relieving the symptoms of endometriosis with prevention of their return during 24 weeks follow-up in the majority of patients. However, results were not significantly different from those achieved with danazol 600 mg/d.
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Context Preclinical studies suggest that estrogen affects neural structure and function in mature animals; clinical studies are less conclusive with many, but not all, studies showing a positive influence of estrogen on verbal memory in postmenopausal women. Objective To investigate the effects of estrogen on brain activation patterns in postmenopausal women as they performed verbal and nonverbal working memory tasks. Design Randomized, double-blind, placebo-controlled, crossover trial from 1996 through 1998. Setting Community volunteers tested in a hospital setting. Patients Forty-six postmenopausal women aged 33 to 61 years (mean [SD] age, 50.8 [4.7] years). Intervention Twenty-one-day treatment with conjugated equine estrogens, 1.25 mg/d, randomly crossed over with identical placebo and a 14-day washout between treatments. Main Outcome Measures Brain activation patterns measured using functional magnetic resonance imaging during tasks involving verbal and nonverbal working memory. Results Treatment with estrogen increased activation in the inferior parietal lobule during storage of verbal material and decreased activation in the inferior parietal lobule during storage of nonverbal material. Estrogen also increased activation in the right superior frontal gyrus during retrieval tasks, accompanied by greater left-hemisphere activation during encoding. The latter pattern represents a sharpening of the hemisphere encoding/retrieval asymmetry (HERA) effect. Estrogen did not affect actual performance of the verbal and nonverbal memory tasks. Conclusions Estrogen in a therapeutic dosage alters brain activation patterns in postmenopausal women in specific brain regions during the performance of the sorts of memory function that are called upon frequently during any given day. These results suggest that estrogen affects brain organization for memory in postmenopausal women.
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Goserelin (Zoladex®), a gonadotropin-releasing hormone analogue, reduces plasma/serum estrogen levels in pre- or perimenopausal women (to postmenopausal levels), and is indicated in hormone receptor-positive early breast cancer in this population group. Adjuvant goserelin monotherapy has similar efficacy to adjuvant chemotherapy in pre- or perimenopausal women with early, hormone receptor-positive breast cancer. Furthermore, the addition of goserelin to adjuvant chemotherapy appeared to offer an advantage over chemotherapy alone in younger patients. Fewer patients remained amenorrheic after goserelin therapy than after chemotherapy. Complete endocrine blockade provided by the addition of tamoxifen to therapy including goserelin appears to improve outcomes. Thus, goserelin offers a valuable addition to the currently available options for treating pre- or perimenopausal women with hormone therapy-responsive early breast cancer, particularly for women wishing to regain ovarian function after treatment. Pharmacological Properties Goserelin is a gonadotropin-releasing hormone (GnRH) analogue. Initial occupation of GnRH receptors by goserelin results in a transient increase in plasma/ serum luteinising hormone and follicle-stimulating hormone levels. The subsequently decline to pretreatment levels or lower within 3 weeks of continued goserelin administration because of drug-induced downregulation of the anterior pituitary gland. This results in a decrease in plasma/serum estradiol levels to within the postmenopausal range generally within 14 days of depot administration. Formulated as a biodegradable sustained-release depot injection, goserelin 3.6mg is administered subcutaneously every 28 days. In women with gynaecological disorders, the mean peak serum concentration (1.35–1.84 μg/L) was reached 12–15 days after administration of goserelin; there was no accumulation of the drug with monthly injections for up to 6 months. Protein binding of goserelin in human plasma is low. The release of goserelin from the depot formulation was complete over a 4-week period. After extensive metabolism, goserelin is excreted primarily in the urine. Mean total body clearance in women with gynaecological disorders was 8.68–9.65 L/h after goserelin 3.6mg administered as single or multiple depot injections. Therapeutic Efficacy The efficacy of goserelin in the adjuvant treatment of early breast cancer in premenopausal or perimenopausal women has been evaluated in several randomised, multicentre, nonblind trials (n = 244–2710), which included patients with hormone receptor-positive (GROCTA 02, ABCSG 5 and INT 0101 trials) or mixed receptor status (IBCSG VIII, ZIPP, ZEBRA and MAM1 trials) disease. Goserelin was equivalent to chemotherapy in terms of disease-free survival in women with hormone receptor-positive early breast cancer in the ZEBRA and IBCSG VIII trials. While adjuvant chemotherapy followed by goserelin was no better than chemotherapy alone in the overall trial population with hormone receptor-positive breast cancer (INT 0101 and IBCSG VIII), the addition of goserelin may have improved outcomes for a subgroup of women aged
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Even in the absence of an experimental effect, functional magnetic resonance imaging (fMRI) time series generally demonstrate serial dependence. This colored noise or endogenous autocorrelation typically has disproportionate spectral power at low frequencies, i.e., its spectrum is -like. Various pre-whitening and pre-coloring strategies have been proposed to make valid inference on standardised test statistics estimated by time series regression in this context of residually autocorrelated errors. Here we introduce a new method based on random permutation after orthogonal transformation of the observed time series to the wavelet domain. This scheme exploits the general whitening or decorrelating property of the discrete wavelet transform and is implemented using a Daubechies wavelet with four vanishing moments to ensure exchangeability of wavelet coefficients within each scale of decomposition. For -like or fractal noises, e.g., realisations of fractional Brownian motion (fBm) parameterised by Hurst exponent 0 < H < 1, this resampling algorithm exactly preserves wavelet-based estimates of the second order stochastic properties of the (possibly nonstationary) time series. Performance of the method is assessed empirically using -like noise simulated by multiple physical relaxation processes, and experimental fMRI data. Nominal type 1 error control in brain activation mapping is demonstrated by analysis of 13 images acquired under null or resting conditions. Compared to autoregressive pre-whitening methods for computational inference, a key advantage of wavelet resampling seems to be its robustness in activation mapping of experimental fMRI data acquired at 3 Tesla field strength. We conclude that wavelet resampling may be a generally useful method for inference on naturally complex time series. Hum. Brain Mapping 12:61–78, 2001. © 2001 Wiley-Liss, Inc.
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Estrogen is thought to have an impact on both psychological well being and cognitive function. The biological basis to this is not fully understood, but may involve estrogen's interactions with central serotonergic (5-HT) systems. Therefore, we studied the effect of long-term estrogen hormone replacement therapy (ERT) on central 5-HT tone in healthy postmenopausal women and made comparisons with young women. Prolactin (PRL) responses to the specific 5-HT releasing and re-uptake inhibiting agent, d-fenfluramine, were measured in three groups of healthy women: 11 young, 11 postmenopausal on long-term ERT, and 11 postmenopausal ERT naı̈ve. PRL responses were significantly decreased in ERT naı̈ve women compared to young healthy women. In contrast, PRL responses were not different between estrogen-treated and young women. Overall, there was a significant relationship between older age and lower PRL responsivity. These results suggest that central 5-HT tone is reduced in healthy postmenopausal women who are ERT naı̈ve, but not in postmenopausal women who have received prolonged estrogen treatment. Estrogen may modulate age-related changes in 5-HT tone. This may partly explain why estrogen can decrease vulnerability to mood disorders and cognitive changes in postmenopausal women.
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The use of surrogate data has become a crucial first step in the study of nonlinearity in time series data. A widely used technique to construct surrogate data is to randomize the phases of the data in the Fourier domain. In this paper, an alternative technique based on the resampling of wavelet coefficients is discussed. This approach exploits between scale correlations that exist within nonlinear data but which are either absent or weak in stochastic data. It proceeds by transforming the data into the wavelet domain and permuting the wavelet coefficients. Experimental and numerical time series data are used to demonstrate that the performance of the wavelet resampling technique is comparable to phase randomization in terms of the preservation of linear properties, removal of nonlinear structure and computational demands. However, the wavelet technique may have specific and distinct advantages in the application to complex data sets, such as numerical analysis of turbulence and experimental brain imaging data, where wavelets give a more parsimonious representation of spatio-temporal patterns than Fourier modes. It is shown that different techniques of resampling the data in the wavelet domain may optimize the construction of surrogate data according to the properties of the experimental time series and computational constraints.
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To compare the efficacy and safety of goserelin depot and danazol for endometriosis. Open, randomized comparative trial. Multicenter European academic clinical institutions. A total of 307 patients with laparoscopically diagnosed endometriosis were randomized to goserelin (n = 204) or danazol (n = 103); 249 patients underwent second look laparoscopy (175 received goserelin and 74 danazol) and were analyzed for efficacy. A 3.6-mg depot of goserelin monthly subcutaneously or oral danazol 200 mg three times a day administered for 24 weeks. Efficacy assessments were based on changes in visible deposits at laparoscopy before and after treatment and subjective symptom scores at 4-week intervals during treatment and 8-week intervals after treatment for up to 24 weeks. Safety was assessed by adverse event reporting and clinical laboratory measures. There were similar proportions of symptomatic (73%) and asymptomatic (but infertile) (27%) and comparable distribution of different severity of endometriosis randomized to each treatment. Significantly fewer patients randomized to goserelin (6.4%) withdrew during treatment compared with 20.4% randomized to danazol (P less than 0.05). There were significantly reduced visible deposits of endometriosis found post-treatment (P less than 0.0001) within each group but no differences between the treatments. The mean total subjective symptoms scores remained significantly less than entry at 24 weeks post-treatment (P less than 0.05). Hypoestrogenic side effects were more common in those receiving goserelin, particularly hot flushes, but anabolic/androgenic side effects of weight gain and muscle cramps were more common in those receiving danazol. The monthly administered 3.6-mg depot preparation of goserelin was highly effective at inducing resolution of endometriotic implants and relieving the symptoms of endometriosis with prevention of their return during 24 weeks follow-up in the majority of patients. However, results were not significantly different from those achieved with danazol 600 mg/d.
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Introduction ON JUNE 24, 1971, Andrew V. Schally announced the determination of the primary structure of porcine GnRH at The Endocrine Society Meeting in San Francisco. This announcement was followed by publications by Matsuo et al. (1, 2) and Baba et al. (3) on the proposed amino acid sequence for porcine GnRH and its synthesis and by Burgus et al. (4) who characterized ovine GnRH and found the sequence to be identical with that of porcine GnRH. The physiological and therapeutic importance attributed to the discovery of the new substance was greatly increased by the prospect of the design of potent and long acting GnRH agonists and antagonists. Since that time more than 2000 analogs of GnRH have been synthesized. The impact of research of GnRH and its analogs on clinical medicine recently led Ziporyn (5) to note, “There's almost no subspecialty of medicine that will be left untouched by the [research] advances associated with LHRH or its analogs.” It is the intent of this article to provide a historical ...
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STUDY-PLAN: an open study aimed at evaluating the results of a short term therapy (3 months) with Goserelin depot as a medical treatment of premenopausal dysfunctional uterine bleeding. 60 premenopausal women (aged 36-50) with dysfunctional uterine bleeding, presenting simple endometrial hyperplasia. after the treatment, spontaneous menstrual bleeding recurred in 57/60 patients, while 3/60 (5%) patients remained amenorrheal during the whole period of follow-up, showing a postmenopausal hormonal pattern. In the first post-therapy menstrual cycle all the 57 patients had a bleeding score < 100; patients relapsing during the second, third and fourth cycle were respectively 2/54 (3.7%), 5/48 (10.7%) and 17/38 (44.7%). The fourth post-therapy cycle was delayed 6-9 months after the last injection of Goserelin. Both the mean blood loss and the mean duration of bleeding were significantly reduced in all post-therapy cycles. Eleven patients were anaemic before therapy (Hb < 12 g%); Goserelin treatment resulted in a normalization of the hematological parameters. At the end of treatment a small area of hyperplasia persisted in only 4/60 patients (6.7%). Localised or diffused hyperplasia were found respectively in 5/54 (9.3%) and in 1/54 patients (1.9%) at three months, and in 5/48 (10.4%) and 4/48 (8.3%) at a six-month follow-up. Side effects were infrequent. the long symptom-free period and the low incidence of side effects indicates Goserelin depot as a valuable medical treatment for dysfunctional uterine bleeding.
Article
The objective of this study was to determine the effectiveness of ovarian suppression by a GnRH agonist analogue in 32 women with prospectively confirmed severe premenstrual tension. The design was a randomized, double-blind study comparing goserelin 3.6 mg with placebo, both given as a monthly s.c. injection for 3 months. Self-assessment was by daily visual analogue scales (VAS) for anxiety and depression, daily quantitative symptom rating for breast discomfort, swelling, irritability, tension, depression and by monthly Hospital Anxiety and Depression (HAD) scales. Of the 16 women in each group, 15 completed active and 12 completed placebo therapy. Median symptom scores for whole cycles showed a significant reduction of breast discomfort and swelling during active treatment, with no significant improvement in psychological symptoms. Analysis by cycle phase showed that for individual subjects, pre-treatment differences in VAS scores for anxiety and depression were abolished in a significantly greater proportion of actively treated cycles. Within-group comparisons showed a marked placebo effect and, comparing the two groups, differences reached significance only during treatment cycle 1 and the first post-treatment cycle for anxiety with no significant differences for depression. It was concluded that while suppression of ovarian activity with a gonadotrophin-releasing hormone analogue dampens down cyclical mood swings, it has a more marked effect on the physical components of the premenstrual syndrome. Results reconfirm the positive role of placebo in the management of this condition.
Article
The study investigated the neuropsychological status of women with induced hypoestrogenism. An ABA design was employed in which neuropsychological measures were repeated prior to, during, and after induction of hypoestrogenism with leuprolide acetate. The study took place in a medical school affiliated in vitro fertilization clinic. Leuprolide acetate was administered to all subjects as part of in vitro fertilization. Eighteen women receiving in vitro fertilization treatment underwent neuropsychological testing before, during, and after treatment with leuprolide acetate and gonadotrophins. The neuropsychological test battery was selected on the basis of previous patients' symptomatic complaints during periods of hypoestrogenism with leuprolide acetate. Depending upon the tests administered, some individuals showed significant cognitive deficits during therapy particularly in the areas of memory, fine motor coordination, and two-point discrimination. Two of the 18 subjects showed very substantial neuropsychological sequelae including memory gaps and disturbances in a variety of neuropsychological test performances. However, in terms of group statistics, only two-point discrimination and delayed recall memory test performance proved significant. Not all measures were sensitive for the group, as many tests displayed a balance between individuals who showed practice effects and those who showed detrimental effects. For a substantial portion of individuals, hypoestrogenism can result in statistically significant or clinically noteworthy problems with memory, dexterity, and two-point discrimination.
Article
To evaluate the efficacy of goserelin versus a low-dose cyclic oral contraceptive (OC) in improving pelvic pain in women with endometriosis and to compare recurrence of symptoms during follow-up. Open-label, randomized trial. University hospital endometriosis center. Fifty-seven women with moderate or severe pelvic pain and laparoscopically diagnosed endometriosis. Six-month treatment with goserelin depot (n = 29) or a low-dose cyclic OC (n = 28) followed by 6-month follow-up. Variation in severity of symptoms during treatment and at the end of follow-up as shown by a linear analog scale and a verbal rating scale. At 6 months of treatment, a significant reduction in deep dyspareunia was observed in both groups, with goserelin superior to the OC at linear analog scale assessment. Nonmenstrual pain was diminished on both scales without differences between treatments. Women taking the OC experienced a significant reduction in dysmenorrhea. At the end of follow-up, symptoms reappeared without differences in severity between the groups. Low-dose cyclic OCs may be a valuable alternative for the treatment of dysmenorrhea and nonmenstrual pain associated with endometriosis. Symptoms recurred in most subjects 6 months after drug withdrawal.
Article
Findings from basic neuroscience have provided information on the effects of estrogen on brain morphology and chemistry that explain how this sex steroid may influence brain function. The clinical literature shows that estrogen enhances mood and specific aspects of cognitive functioning in postmenopausal women. There is also evidence that estrogenic effects on various psychological functions are dissociable and specific. Although several recent epidemiologic case-control studies have suggested a protective effect of estrogen against Alzheimer disease, these findings need to be verified by prospective, controlled investigations.
Article
To assess whether suppression of ovarian function by a gonadotrophin releasing hormone (GnRH) analogue could assist in the diagnosis of chronic pelvic pain in women with residual ovaries. Uncontrolled, observational study. District general hospital (seven women) and teaching hospital (one woman). Eight women with residual ovaries and chronic pelvic pain. Goserelin 3.6 mg every 28 days was used followed by surgery to remove residual ovaries. The women's response to goserelin and surgery (12 months or more post-operatively) was assessed clinically. RESULTS. Goserelin was associated with resolution of pelvic pain in the six women who obtained relief of pain with oophorectomy. The only woman who did not respond to goserelin also failed to gain relief with surgery. One woman who responded to goserelin declined surgery. Suppression of ovarian function by GnRH analogues may allow differentiation of pelvic pain caused by the residual ovary syndrome from other causes. This would enable selection of cases likely to benefit from surgery, avoiding potentially difficult surgery in women who will gain little or no relief of symptoms with surgery. Only eight cases are reported and a randomised controlled trial would be required to determine the place of GnRH agonists in the treatment of the residual ovary syndrome.
Article
To study the effect of GnRH agonist (GnRH-a) treatment on memory and to assess the role of psychological factors. A randomized prospective study. An academic teaching hospital. Women with endometriosis and infertility or endometriosis alone. Memory Observation Questionnaire, Profile of Mood States, Health Concerns scale, a weekly diary of adverse effects. Perceived memory functioning decreased during GnRH-a administration and by the final week of treatment 44% of women reported moderate to marked impairment in comparison to community norms. Prospective memory was most affected and withdrawal of GnRH-a treatment resulted in a return to normal memory functioning. Impairment was not related to excessive health concerns or mood changes and was uncorrelated with other adverse effects. Memory disruption may be a more common side effect of GnRH-a treatment than currently is recognized. Problems were temporary and more likely a result of rapid estrogen depletion than a consequence of mood, somatic distress, or personality factors.
Article
Treatment of women with uterine myomas with GnRH agonists results in symptoms of hypoestrogenism which can be prevented by concurrent "add-back" estrogen administration. We took advantage of these induced endocrine changes to investigate their effects on cognitive functioning in young women with myomas. Nineteen women with uterine myomas were tested before treatment. They all received the GnRH agonist, leuprolide acetate depot (LAD), every 4 weeks for 12 weeks and were then randomized to receive LAD plus estrogen or LAD plus placebo every 4 weeks for 8 additional weeks. Levels of all sex hormones decreased after 12 weeks of LAD treatment (P < 0.01), and only estradiol (E2) levels increased (P < 0.01) following 8 weeks of subsequent treatment in the group that received LAD plus E2. Scores on neuropsychological tests of verbal memory decreased from pretreatment to 12 weeks posttreatment with LAD (P < 0.05). These memory deficits were reversed in the group that received LAD plus E2 for 8 weeks coincident with an increase in plasma E2, whereas memory scores remained depressed in the group that received LAD plus placebo. These findings are consistent with those from studies on surgically menopausal women and strongly suggest that estrogen serves to maintain verbal memory in women. These results provide support for the efficacy of add-back estrogen regimens in women treated with GnRH agonists and also imply that estrogen may be important for maintaining memory in the postmenopause.
Article
Using functional magnetic resonance imaging (fMRI), we mapped brain activity in six normal volunteers during two silent verbal fluency tasks, one with a phonemic (letter) cue and one with a semantic (category) cue. In comparison with resting state, both tasks activated the anterior triangular portion of the left inferior frontal gyrus (IFG or F3, for third frontal gyrus) and the left thalamus. There were also areas activated in one task but not in the other: the posterior opercular portion of the left IFG for phonemic fluency, and the left retrosplenial region for semantic fluency. Our findings concur with normal psychophysical data and neuropsychological observations to suggest the recruitment of two overlapping but dissociable systems for the two tasks, and demonstrate functional heterogeneity within the left IFG (Broca's area), where the opercular portion is responsible for obtaining access to words through a phonemic/articulatory route.
Article
We report a novel method to identify brain regions generically activated by periodic experimental design in functional magnetic resonance imaging data. This involves: 1) registering each of N individual functional magnetic resonance imaging datasets in a standard space; 2) computing the median standardised power of response to the experimental design; 3) testing median standardised power at each voxel against its nonparametrically ascertained distribution under the null hypothesis of no experimental effect; and 4) constructing a generic brain activation map. The method is validated by analysis of 6 null images, acquired under conditions when the null hypothesis was known to be true; 8 images acquired during periodic auditory-verbal stimulation; and 6 images acquired during periodic performance of a covert verbal fluency task.
Article
Findings from basic neuroscience have elucidated mechanisms of action of estrogen on the structure and function of brain areas known to be critically involved in memory. Controlled clinical studies of the administration of estrogen to postmenopausal women have found that estrogen enhances verbal memory and maintains the ability to learn new material. These findings are supported by those from investigations of healthy, elderly, women and by results of a study in which younger women received a gonadotropin releasing-hormone analog that suppressed ovarian function. The specificity of the estrogenic effect on cognitive functions is consistent with known sex differences in cognitive abilities and suggests that, in adulthood, estrogen serves to activate neural pathways established under the influence of this steroid hormone during prenatal life.
Article
Reports that estrogen may protect against age-associated memory decline and Alzheimer's Disease have kindled interest in the effects of estrogen replacement therapy (ERT) on cognition and brain function. As part of a 9-year study in the Baltimore Longitudinal Study of Aging, we are performing annual magnetic resonance imaging, positron emission tomography (PET), and neuropsychological assessments to examine brain structure and function in individuals aged 55 and older. PET measurements of regional cerebral blood flow (rCBF) are obtained under 3 conditions: rest and verbal and figural delayed recognition memory tasks. Fifteen women receiving ERT (with or without the addition of progesterone) were compared with a matched sample of 17 untreated women. There were no significant differences between groups in regional brain volumes or ventricular size. However, ERT users and nonusers showed significant differences in PET-rCBF relative activation patterns during the memory tasks. During verbal memory processing, there were significant interactions in rCBF activations for the right parahippocampal gyrus, right precuneus, right frontal regions, and left hypothalamus. During figural memory processing, significant interactions were observed for right parahippocampal and inferior parietal regions and for left visual association and anterior thalamic regions. ERT users also showed better performance on neuropsychological tests of figural and verbal memory and on some aspects of the PET activation tests, although the two groups did not differ in education, overall verbal ability, or performance on other neuropsychological tests. These findings confirm our previous observation of the beneficial effects of ERT on figural memory. Moreover, differences in rCBF activation patterns between ERT users and nonusers suggest an area for future research to examine mechanisms through which ERT may influence memory and other cognitive abilities.
Article
Movement-related effects in realigned fMRI timeseries can be corrected by regression on linear functions of estimated positional displacements of an individual subject's head during image acquisition. However, this entails biased (under)estimation of the experimental effect whenever subject motion is not independent of the experimental input function. Methods for diagnosing such stimulus-correlated motion (SCM) are illustrated by application to fMRI data acquired from 5 schizophrenics and 5 normal controls during periodic performance of a verbal fluency task. The schizophrenic group data were more severely affected by SCM than the control group data. Analysis of covariance (ANCOVA) was used, with a voxelwise measure of SCM as a covariate, to estimate between-group differences in power of periodic signal change while controlling for variability in SCM across groups. Failure to control for SCM in this way substantially exaggerated the number of voxels, apparently demonstrating a between-group difference in task response.
Article
Preclinical studies suggest that estrogen affects neural structure and function in mature animals; clinical studies are less conclusive with many, but not all, studies showing a positive influence of estrogen on verbal memory in postmenopausal women. To investigate the effects of estrogen on brain activation patterns in postmenopausal women as they performed verbal and nonverbal working memory tasks. Randomized, double-blind, placebo-controlled, crossover trial from 1996 through 1998. Community volunteers tested in a hospital setting. Forty-six postmenopausal women aged 33 to 61 years (mean [SD] age, 50.8 [4.7] years). Twenty-one-day treatment with conjugated equine estrogens, 1.25 mg/d, randomly crossed over with identical placebo and a 14-day washout between treatments. Brain activation patterns measured using functional magnetic resonance imaging during tasks involving verbal and nonverbal working memory. Treatment with estrogen increased activation in the inferior parietal lobule during storage of verbal material and decreased activation in the inferior parietal lobule during storage of nonverbal material. Estrogen also increased activation in the right superior frontal gyrus during retrieval tasks, accompanied by greater left-hemisphere activation during encoding. The latter pattern represents a sharpening of the hemisphere encoding/retrieval asymmetry (HERA) effect. Estrogen did not affect actual performance of the verbal and nonverbal memory tasks. Estrogen in a therapeutic dosage alters brain activation patterns in postmenopausal women in specific brain regions during the performance of the sorts of memory function that are called upon frequently during any given day. These results suggest that estrogen affects brain organization for memory in postmenopausal women.
Article
This study investigated the effect of estrogen treatment on working memory and reference memory of female rats. In addition, the impact of estrogen on the sensitivity of these two types of memory to the cholinergic antagonist scopolamine was investigated. At 35 days of ages, rats were ovariectomized and implanted chronically with Silastic capsules containing either 25% crystalline estradiol or 100% cholesterol. Thirty days after surgery, animals were trained on an eight-arm radial maze with four arms baited to assess both working and reference memory performance. Following training, females were given scopolamine hydrobromide (0.2 mg/kg i.p.) prior to retesting on the task. Results indicated that estrogen treatment improved working memory performance during maze acquisition but did not affect reference memory performance. Scopolamine treatment impaired performance on the working memory component, but not the reference memory component, while estrogen prevented the impairment of working memory by scopolamine. Results support previous evidence that estrogen selectively enhances performance on tasks that depend on working memory.
Article
To evaluate the technical feasibility, oncological efficacy and intraoperative and postoperative morbidity of laparoscopic radical prostatectomy. We describe an original technique of laparoscopic radical prostatectomy performed in 40 patients between 26th January and 12th October, 1998. Radical prostatectomy was performed entirely by laparoscopy in 35 patients (87.5%) and only one conversion was performed in the last 26 patients (4%). Pelvic lymphadenectomy was performed in the light of preoperative staging data in 14 patients (35%). The median total operating time was 270 min. The only major complication was a rectal injury (patient 8), sutured laparoscopically with an uneventful postoperative course. Postoperative vesical catheterization lasted an average of 7.65 days. Seven patients were transfused (17.5%) with an average of 2.8 units of packed cells (range: 2-3). The reduction of postoperative pain is an element allowing for a rapid discharge of the patients by the 3rd postoperative day. The oncological results were as follows: 36 patients had a pT2 tumor (90%); prostate tumor was staged as N0 in 14 cases and NX in 26 cases. Surgical margins were negative in 33 patients (82.5%). Two patients had a doubtful resection margin (1 at the apex and 1 at the bladder neck) and 5 patients had positive margins. The last PSA level was undetectable (<0.1 ng/ml) in 26 (89.7%) of the 29 patients in whom PSA level was available more than 1 month after the operation. Functional results are not yet available and will be published later. Radical prostatectomy is an operation which can be routinely performed by laparoscopy by a team experienced with this technique. Operative and postoperative morbidity was low. Short-term oncological data appear identical to the results of conventional retropubic surgery. The improvement of operative visibility was considerable allowing a much more precise dissection. The laparoscopic approach appears to represent a technical improvement of the radical prostatectomy if the functional results of this operation improve parallel to the quality of dissection. A long-term follow-up is needed to define definitively the place of this new approach to radical prostatectomy.
Article
There is increasing interest in the use of adjuvant hormonal therapies, which are given after the resection or destruction of all gross disease, in early-stage prostate cancer, as a significant proportion of patients experience progression and/or die from the disease despite undergoing therapy with curative intent. Several retrospective studies suggest that adjuvant hormonal therapy may improve long-term outcome after radical surgery in men with posit