Angelique Flöter Rådestad

Effects of testosterone and estrogen replacement on memory function.

Objective: Testosterone insufficiency has been associated with psychosexual problems, reduced psychological well-being, and negative metabolic consequences, whereas less is known about the effects on cognition. The aim of this study was to investigate the effect of adding testosterone to estrogen therapy on memory functions in oophorectomized women. Methods: In a randomized, double-blind, placebo-controlled design, women with surgically induced menopause (n = 50; mean [SD] age, 54.0 [2.9] y) received estradiol valerate in combination with testosterone undecanoate or placebo. The women were assessed with a self-report questionnaire regarding memory and neuropsychological tests for verbal and spatial episodic memory and incidental learning at baseline, at the time of crossover, and after completion of treatment. Results: Testosterone undecanoate 40 mg added to estrogen therapy had a negative effect on immediate but not delayed verbal memory at 24 weeks. Subjective and objective memory showed some correspondence as the women in the estrogen + placebo treatment group rated decreased everyday memory problems at 24 weeks compared with baseline. This was not observed in the women in the estrogen + testosterone treatment. Verbal attention span deteriorated from baseline with estrogen + placebo treatment but not with the estrogen + testosterone treatment. However, there was no significant treatment effect between the two groups. Conclusions: Adding testosterone to estrogen treatment deteriorated immediate verbal memory compared with estrogen + placebo, while other memory functions were unaffected.

Effects of estrogen and testosterone treatment on serotonin transporter binding in the brain of surgically postmenopausal women – a PET study

Sex hormones and the serotonergic system interact in the regulation of mood, learning, memory and sexual behaviour. However, the mechanisms have not been fully explored. The serotonin transporter protein (5-HTT) regulates synaptic concentrations of serotonin and is a primary target for selective serotonin reuptake inhibitors. The aim of this study was to explore how estrogen treatment alone or in combination with testosterone affects 5-HTT binding potentials measured by positron emission tomography (PET) in specific brain regions of postmenopausal women. Ten healthy surgically postmenopausal women (years since oophorectomy 7.5 ± 4.0, mean ± SD) underwent PET examinations at baseline, after three months of estrogen treatment (transdermal estradiol 100 μg/24 hours) and after another three months of combined estrogen and testosterone (testosterone undecanoate 40 mg daily) treatment using the radioligand [(11)C] MADAM developed for examination of the serotonin transporter. The 5-HTT binding potentials decreased significantly in several cortical regions, as well as in limbic and striatal regions after both estrogen treatment alone and combined estrogen/testosterone treatment in comparison to baseline. The observed decrease in 5-HTT could either be due to direct effects on serotonin transporter expression or be the result of indirect adaptation to estrogen and /or testosterone effects on synaptic serotonin levels. Although the mechanism still needs further exploration, the study supports the view that gonadal hormones play a role in serotonin regulated mood disorders.

Cognitive function in association with sex hormones in postmenopausal women

Several studies have suggested gender differences in cognitive function, but data on the association between sex hormones and cognitive function are contradictory. The aim of our randomized double-blind study was to explore the possible relations between cognitive function and serum levels of sex hormones, oxytocin and insulin-like growth factor-I (IGF-I) in postmenopausal women. Two-hundred healthy postmenopausal women were randomly assigned to receive estrogen, testosterone or placebo treatment for 1 month. The associations of spatial ability, verbal fluency and verbal memory with serum levels of estradiol, testosterone, estradiol/testosterone ratio, androstanediol, oxytocin and IGF-I were analyzed. Spatial ability showed a negative correlation with serum estradiol, estradiol/testosterone ratio, oxytocin levels and a positive association with androstanediol levels. Verbal fluency displayed a negative relationship with serum levels of testosterone, IGF-I and a positive with estradiol/testosterone ratio. Verbal memory displayed a positive correlation to androstanediol. Data suggest that not only absolute levels of sex hormones but also the balance between estrogen and testosterone and their metabolites may be important for cognitive function in women.

Effect of estrogen and testosterone replacement therapy on cognitive fatigue

Both estrogen and testosterone insufficiency has been associated with reduced psychological well-being including fatigue. However, hormonal replacement studies on fatigue are rare. Therefore, we wanted to study the effect of testosterone and estrogen replacement therapy on cognitive fatigue and the relation between sex hormone levels and cognitive fatigue in oophorectomized women. Fifty women with surgically induced menopause (mean age: 54.0 ± 2.9 years) were randomly assigned to treatment with estradiol valerate in combination with testosterone undecanoate or placebo for 24 weeks in a double-blind cross-over study. Neuropsychological tests and questionnaires were used to assess cognitive fatigue and psychological well-being. Cognitive fatigue was significantly associated to poor self-rated health and higher body mass index but not to general psychological well-being or sex hormone levels. Treatment with testosterone + estrogen had no significant effect on cognitive fatigue but the results indicated a curvilinear relation for hormonal levels. The estrogen/testosterone ratio was more related to functions rather than high or low hormone levels per se. We found that cognitive fatigue is frequent in oophorectomized women and negatively associated to self-perceived health and positively associated to BMI. A well-balanced ratio between estrogen and testosterone levels may be important for cognitive fatigue.

Testosterone addition to estrogen therapy – Effects on inflammatory markers for cardiovascular disease

Objective. To analyze the effects of testosterone addition to estrogen therapy in comparison with estrogen alone on cardiovascular risk factors in postmenopausal women. Methods. Fifty surgically postmenopausal women were included in this double-blind, placebo-controlled and randomized study to receive daily oral treatment with estradiol valerate 2 mg + placebo (E/P) or estradiol valerate 2 mg + testosterone undecanoate 40 mg (E/T) for 24 weeks and then switched to the other regimen for another 24 weeks. Sex hormones, High sensitivity CRP (hsCRP), Interleukin-6 (IL-6), Tissue necrosis factor (TNF)-α, Insulin-like growth factor binding globulin (IGFBP-1), vascular cell adhesion molecule (VCAM)- 1, and homocysteine were analyzed at baseline and after 6 and 12 months. Results. Estradiol and androgens increased as expected during the treatments. After 6 months of E/P, increases of hsCRP and IGFBP-1 and a decline of VCAM were recorded, whereas IL-6, TNF-α, and homocysteine were unchanged. When testosterone was added to estrogen, the increase of IGFBP-1 and decline in VCAM was similar as with estrogen treatment alone. However, testosterone addition counteracted the estrogen-induced rise in hsCRP but had no effects on IL-6, TNF-α, and homocysteine. Conclusion. Data suggest that testosterone addition to estrogen treatment in postmenopausal women has a modest influence on inflammatory markers and there were no apparent adverse effects. On the contrary, the estrogen-induced increase in hsCRP was suppressed.

Introduction of robot‐assisted radical hysterectomy for early stage cervical cancer: impact on complications, costs and oncologic outcome

The objective was to assess the impact of robot‐assisted radical hysterectomy (RRH) on surgical and oncologic outcome and costs compared with open radical hysterectomy (ORH) at a tertiary referral center in Sweden.

Hormone therapy after uterine cervical cancer treatment: a Swedish population-based study.

ObjectiveThis study aims to assess use of hormone therapy (HT) after cervical cancer treatment in women of premenopause age. MethodsWe identified 837 women aged 45 years or younger at diagnosis of cervical cancer in the Swedish Cancer Register from January 1, 2005 to September 30, 2009 with a minimal follow-up of 1.5 years. Information on cancer treatment (surgical operation, radiotherapy, and/or chemotherapy) was obtained through the National Patient Register. Use of HT was estimated through HT dispensing during follow-up as recorded in the Prescribed Drug Register. Percentage of recommended dose was assessed by frequency of HT dispensing at half-year intervals up to April 1, 2011 or a maximal age of 50 years. ResultsA total of 257 women (31%) received acute estrogen deprivation due to bilateral salpingo-oophorectomy and/or radiotherapy. Among these women, 171 (67%) of 257 had at least one dispensing of HT during the period 0.5 to 1 year after diagnosis, and 118 (46%) of 257 were dispensed 75% or more of the recommended dose. Proportion users decreased to 39% at 4.5 to 5 years after diagnosis (21% with ≥75% of the recommended dose). Women younger than 40 years had a higher prevalence of HT use at 0.5 to 1 year (79%), decreasing to 45% after 4.5 to 5 years. The results did not vary by cancer histology. ConclusionsFewer than half of cervical cancer survivors with therapy-induced early menopause used HT at or close to the recommended dose, and the use decreased during follow-up. Increased awareness of the health benefits of HT for this patient group is needed among professionals and women.

Anti‐Müllerian hormone in premenopausal women following treatment of uterine cervical cancer

In this longitudinal study we prospectively enrolled 32 premenopausal women (ages 23–44 years) with stage I–III uterine cervical cancer undergoing surgery and/or chemoradiation. Serum levels of anti‐Müllerian hormone, follicle‐stimulating hormone and estradiol were examined at baseline and 1 year after treatment. As expected, serum anti‐Müllerian hormone was undetectable after salpingo‐oophorectomy or chemoradiation. After radical hysterectomy and pelvic lymphadenectomy with ovarian preservation serum anti‐Müllerian hormone declined from a mean value of 2.0 ± 1.4 μg/L to 1.1 ± 0.8 μg/L (p = 0.01), representing a 45% reduction, whereas there was no significant change in serum levels of follicle‐stimulating hormone and estradiol. This implies that ovarian function may be affected not only by castrating treatment but also by radical hysterectomy with ovarian preservation. The risk of premature menopause and the potential need of hormone replacement therapy among these women may be overlooked since they no longer menstruate.

Impact of Human Cytomegalovirus Infection and its Immune Response on Survival of Patients with Ovarian Cancer

Human cytomegalovirus (HCMV) has been detected in various types of tumors. We studied the prevalence of HCMV in ovarian cancer and its relation to clinical outcome. Paraffin-embedded tissues obtained prospectively from 45 patients with ovarian cancer and 30 patients with benign ovarian cystadenoma were analyzed for expression of HCMV immediate-early protein (IE) and HCMV tegument protein (pp65) by immunohistochemistry. Plasma was analyzed for HCMV serology. HCMV-IgG levels were higher in patients with ovarian cancer or benign cystadenoma than in age-matched controls (P = .002, P < .0001, respectively). HCMV IgM was detected in 12% of ovarian cancer patients and 3% of patients with benign tumors but was absent in controls. In patients with ovarian cancer, higher IgG levels were associated with better outcomes (P = .04). Extensive HCMV-IE protein expression was detected in 75% of ovarian cancers and 26% of benign tumors; pp65 was detected in 67% of ovarian cancers and 14% of benign tumors. A higher grade of HCMV infection was associated with higher stage of disease. Extensive HCMV-pp65 expression was associated with shorter median overall survival than focal expression (39 versus 42.5 months, P = .03). At study closure, 58% of ovarian cancer patients with focal pp65 expression were alive versus 27% of patients with extensive pp65 expression (P = .03). Thus, HCMV proteins are detected at different levels in ovarian tumors and benign cystadenomas. Ovarian cancer patients with focal HCMV-pp65 expression in their tumors and high IgG levels against HCMV lived longer, highlighting a need for in-depth studies of the oncomodulatory role of HCMV in ovarian cancer.

Mifepristone mediates anti-proliferative effect on ovarian mesenchymal stem/stromal cells from female BRCA 1-/ 2- carriers

Women with hereditary mutation in breast cancer‐associated genes (BRCA1−/2−) have a higher lifetime risk of developing ovarian cancer. Here, we aimed to investigate the effect of mifepristone, a selective progesterone receptor modulator of ovarian mesenchymal stem/stromal cells (MSC) from BRCA1−/2− carriers.