B. von Schoultz

Elective ovarian removal and estrogen replacement therapy — effects on sexual life, psychological well-being and androgen status

Conflicting data have been reported on the psychosexual impact of hysterectomy combined with bilateral oophorectomy. Three age-matched, hysterectomized groups of women were investigated: Group A (n = 33): oophorectomized, not receiving estrogen replacement therapy (ERT); Group B (n = 33): oophorectomized, receiving ERT; and Group C (n = 35): ovaries preserved and not receiving ERT. The McCoy Sexual Rating Scale and the Psychological General Well-Being Index as well as a semi-structured interview were used to assess postoperative experience with respect to libido, vaginal lubrication, ability of getting pleasure from intercourse, and ability to achieve orgasm. Serum concentrations of total and free testosterone, insulin-like growth factor I (IGF-I), sex hormone binding globulin, dehydroepiandrosterone sulfate and 4-androstene-3,17-dione were determined. In oophorectomized women sexual life was impaired as compared to those with intact ovaries and these women complained about less pleasure from coitus, impaired libido and lubrication. Regardless of whether estrogens were administered or not a similar pattern was found, indicating that estrogens are of little value in treating these specific sexual dysfunctions. Oophorectomized women receiving ERT reported less anxiety and depression and more well-being similar to women whose ovaries had been preserved. No correlation was found between psychosexual variables and biochemical androgen markers. However, the IGF-I levels were strongly correlated to sexual activity and responsiveness.

A new methodological approach to the evaluation of quality of life in postmenopausal women

An approach employing a range of standardized questionnaires, which included the Nottingham Health Profile (NHP), the Psychological General Well-Being (PGWB) index and the Mood Adjective Check List (MACL), was used to assess health-related quality of life (QoL) in conjunction with a study comparing two doses of transdermal oestrogen (50 or 100 micrograms/24 h) combined with an oral progestogen (5 mg medroxyprogesterone acetate for 14 days each cycle). In addition to the QoL measures, climacteric symptoms were self-rated and also summarized by means of the Kupperman index. In all, 59 women, median age 52 (39-71) years, who completed 4 months of therapy were evaluated. The use of a battery of standardized questionnaires enabled a comprehensive evaluation to be made of perceived health, well-being and day-to-day functioning. Not only was symptomatic relief, e.g. reduced frequency of sweating episodes, sleep disturbance and hot flushes, observed during treatment, but there were also improvements in terms of sleep, energy and emotions. The frequency of health-related problems associated with paid employment, housework, social life, home life and sex life decreased, indicating enhanced ability to take part in daily activities. The PGWB index showed improvement in the subscales representing well-being, anxiety, depression, vitality, health and self-control, while the mood scales indicated that the women experienced less tension and more satisfaction. Although the results of this study need to be further documented on the basis of a placebo-controlled trial, the findings nevertheless imply that the use of a battery of standardized questionnaires optimizes the possibility of evaluating climacteric complaints reliably before and after treatment.

Mammographic breast density during hormone replacement therapy: effects of continuous combination, unopposed transdermal and low-potency estrogen regimens.

Objective: The aim of this study was to evaluate the impact of different hormone replacement therapy (HRT) regimens on mammographic breast density. Study design: Mammographic density was recorded in women participating in a population-based screening program. At first mammogram, all women were non-users of HRT, and thereafter reported continuous use of the same HRT regimen. The study population comprised 158 women: a total of 52 women were using continuous combined HRT (conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 5 mg); 51 women were using low-dose oral estrogen alone (estriol 2 mg daily); and 55 women were using unopposed transdermal estrogen given as a patch (estradiol 50 μg/24 h). Films were coded and analyzed for mammographic density by an independent radiologist blinded to treatments. Mammographic density was classified according to Wolfe. Results: An increase in mammographic density was much more common among women taking continuous combined HRT (40%) than for those using oral low-dose estrogen (6%) and transdermal (2%) treatment. The increase in density was already apparent at the first visit after starting HRT. During long-term follow-up, there was very little change in mammographic status. Conclusion: HRT regimens were shown to have different effects on the normal breast. There is an urgent need to clarify the biological nature and significance of a change in mammographic density during treatment and, in particular, its relation to symptoms and breast cancer risk.

Breast Cell Proliferation in Postmenopausal Women During HRT Evaluated Through Fine Needle Aspiration Cytology

The basis of breast cancer risk associated with hormonal therapies may lie in the regulation of cell proliferation. In a prospective, double-blind, randomized study postmenopausal women were given continuous combined hormone replacement therapy (HRT) either as estradiol valerate 2 mg/dienogest 2 mg, (E2V/DNG) or estradiol 2 mg/noretisterone acetate 1 mg (E2/NETA) for 6 months. Fine needle aspiration (FNA) biopsies were used for immunocytochemical analysis of breast cell proliferation before and during treatment. From 45 women completing the study 135 biopsies were obtained. In the total material there was a more than 4-fold increase in proliferation between baseline and 3 months (p < 0.001). The mean percentage of MIB-1 positive breast cells increased from 2.2 to 9.1%. In some individual women values were as high as 25%. No further increase was recorded at 6 months. While numerical values were somewhat lower in the E2V/DNG group, there were no significant differences between treatments. There was a positive correlation between breast cell proliferation (MIB-1%) and circulating levels of both estradiol (rs = 0.54, p < 0.01) and estrone (rs = 0.53, p < 0.01) after 3 and 6 months of treatment. No correlations with other endogenous hormones, proteins or with the two exogenous progestogens dienogest and norethisterone were observed. Increased breast cell proliferation should probably be regarded as an unwanted side-effect during HRT. Means to identify those women with the most pronounced proliferative response should be developed. The FNA biopsy technique may be a useful tool to monitor and evaluate the proliferative response to HRT in the normal breasts of postmenopausal women.

A comparative study of breast cell proliferation during hormone replacement therapy : effects of tibolon and continuous combined estrogen-progestogen treatment

Objective To use the fine-needle aspiration (FNA) biopsy technique to compare the effects of tibolone, conventional hormone replacement therapy (HRT) and placebo on breast cell proliferation in postmenopausal women. Methods A total of 91 women were randomized to receive either estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA), tibolone 2.5 mg or placebo for 6 months in a prospective double-blind trial. Breast cell proliferation was assessed using the Ki-67/MIB-1 monoclonal antibody. Results From the 83 women who completed the study, a total of 166 FNA biopsies were obtained, and 118 of these aspirates (71%) were evaluable for MIB-1 content. Women with assessable biopsies were younger, had a lower body mass index, and had higher levels of sex hormone binding globulin and insulin-like growth factor-I than women in whom the cell yield was insufficient. During treatment with E2/NETA, there was an increase in proliferation (percentage of MIB-1) from a mean value of 2.2 to 6.4% after 6 months (p < 0.01). No significant changes were recorded during treatment with tibolone or placebo. There was a negative association between proliferation and serum levels of total (rs = −0.29, p < 0.05) and free (rs = −0.31, p < 0.03) testosterone. Conclusions Tibolone seems to have little influence on breast cell proliferation.

Effects of Long-Term HRT and Tamoxifen on the Expression of Progesterone Receptors A and B in Breast Tissue from Surgically Postmenopausal Cynomolgus Macaques

Estrogen is a well-known mitogen in breast epithelium but the role of progesterone is complex and incompletely understood. In contrast to what is seen in the endometrium, combined estrogen/progestogen treatment for postmenopausal replacement (HRT) may carry a risk for breast cancer beyond that of estrogen alone. The ratio of the two progesterone receptor (PR) isoforms, PRA/PRB may define the response to progesterone in reproductive tissues. In a primate model for long-term HRT, surgically, postmenopausal cynomolgus macaques were treated for 35 months with conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), CEE + MPA and tamoxifen (n=5 in all groups). The immunohistochemical expression of PRA, PRB and the androgen receptor (AR) in breast tissue was quantified by image analysis. Over all, the total PR immunostaining in glandular epithelium was more abundant during CEE (mean 12%) and tamoxifen (11%) treatment as compared to CEE/MPA (5%), MPA (4%) and untreated controls (6%). Differences in PRB expression were observed between treatment groups (p<0.05). In the CEE group levels of PRA were unchanged while there was a decline in the CEE/MPA group. The mean PRA/PRB ratio in the CEE group was 2.7 and in the CEE/MPA group 0.2. Treatment with tamoxifen had effects similar to those of estrogen. There was in all groups a weak positive nuclear AR immunostaining. This is the first in vivo study on the effects on long-term hormonal treatment on the expression of PR isoforms in normal primate breast tissue. The results suggest that hormonal treatments have a different influence on the PRA/PRB balance in the breast.

IVF outcome in women with endometriosis in relation to tumour necrosis factor and anti-Müllerian hormone.

This study reports on anti-Müllerian hormone (AMH) in serum and follicular fluid (FF) in relation to inflammatory parameters in women with and without endometriosis undergoing IVF. Serum and FF samples were obtained from 72 women, with (n = 34) and without (n = 38) endometriosis, undergoing IVF. The concentrations of AMH, FSH, tumour necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF) and several interleukins were analysed. Women with endometriosis had significantly lower AMH in serum and FF (serum: 6.38 versus 12.8 pM; P < 0.01, FF: 14.0 versus 19.6 pM; P < 0.05). TNF was increased in FF (40.0 versus 30.8 pg/ml, P < 0.05) from women with endometriosis and significantly higher concentrations of IL-15 and GM-CSF were detected in FF (both P < 0.05). During IVF, women with endometriosis responded well to FSH but had lower fertilization rates. Women with endometriosis have elevated concentrations of several cytokines in FF. They respond adequately to exogenous FSH but may have impaired oocyte quality, reflected in lower fertilization rates, presumably resulting from an inflammatory process in the ovaries. Further studies are needed to elucidate the role of AMH in predicting ovarian reserve in women with endometriosis.

Collagen metabolism markers as a reflection of bone and soft tissue turnover during the menstrual cycle and oral contraceptive use

Two different groups of women, 23 healthy young adults and 13 women with chronic posterior pelvic pain, were studied before and during use of oral contraceptives (OC). Collagen metabolism markers-here, the amino-terminal propeptide of type I procollagen, the carboxy-terminal telopeptide of type I collagen, and the amino-terminal of procollagen type III-as well as hormones and other endocrine factors indicating the balance between androgen expression/anabolism and catabolism of the subjects (testosterone, sex-hormone binding globulin, and insulin-like growth factor I were measured. Type I procollagen, the carboxy-terminal telopeptide of type I collagen, and the amino-terminal of procollagen type III were all significantly decreased during OC use. These findings implicate OC use-induced changes in collagen type I and III turnover. A shift in the anabolic/catabolic balance was also recorded indicating a less anabolic situation during OC use.

Neutral effect of ultra-low-dose continuous combined estradiol and norethisterone acetate on mammographic breast density

Objective To compare the effects of two different ultra-low doses of continuous combined hormone therapy and placebo on mammographic breast density in postmenopausal women. Methods A subpopulation of 255 postmenopausal women from the CHOICE trial were randomly assigned to 0.5 mg 17β-estradiol (E2) + 0.25 mg norethisterone acetate (NETA), 0.5 mg E2 + 0.1 mg NETA, or placebo. Women using hormone replacement therapy (HRT) up to 2 months prior to the study were excluded; 154 women fulfilled the inclusion criteria. Mammograms were performed at baseline and after 6 months. Breast density was evaluated by visual classification scales and a computer-assisted digitized technique. Results No significant differences were detected between the active treatment groups and the placebo group in the digitized quantification. The mean baseline values for density around 20% were unchanged after 6 months. Also, visual classifications showed no increase in breast density in any study group. Conclusion In contrast to currently available bleed-free regimens, the new ultra-low-dose combination of 0.5 mg E2 and 0.1 mg NETA seems to have very little or even a neutral effect on the breast. Both digitized quantification and visual assessment of breast density were unchanged after 6 months. Larger prospective studies should be performed to confirm this new finding.

Serum lipids in oophorectomized women during estrogen and testosterone replacement therapy

OBJECTIVE To evaluate the effects of giving testosterone undecanoate (TU) in addition to estrogen replacement on serum lipids in oophorectomized women. METHOD Women with surgically induced menopause (n = 50) were randomly assigned to oral treatment with 2 mg of estradiol valerate in combination with 40 mg of TU or placebo for 24 weeks. The study was double-blind with cross-over to the other regimen for further 24 weeks of treatment. Forty-four women completed the study. Their serum concentrations of total, high density lipoprotein (HDL)- and low density lipoprotein (LDL)-cholesterol, triglycerides, lipoprotein-(a) (Lp-(a)), total testosterone, estradiol and sex hormone-binding globulin (SHBG) were analyzed at baseline and after 24 weeks of each treatment. RESULTS Serum levels of total testosterone increased markedly from a baseline mean of 0.8-4.9 nmol/l during testosterone addition. The levels of free testosterone significantly increased during the combined treatment and fell when given estrogen alone. Total and LDL-cholesterol levels were significantly reduced by both treatments as also were those of Lp-(a) although the difference was not significant. We found a 13% reduction in HDL-cholesterol levels when testosterone was added, but no change with estrogen alone. Triglyceride levels were increased by estrogen treatment, but not affected by the combination of estrogen plus testosterone. CONCLUSIONS These findings suggest that 40 mg of TU can be given in addition to estrogen replacement with only little side-effects on the pattern of circulating lipids. Although supraphysiological concentrations of testosterone were induced a significant reduction in total and LDL-cholesterol levels occurred.