28 July, 2014

The average age of natural menopause is about 51 years. In the absence of hormone therapy, systemic exposures to ovarian hormones are greatly reduced after menopause, with consequences that vary by organ or tissue. Health-related effects are likely to be more pronounced after premature menopause, defined by menopause at age 40 years or younger.

Potential effects of premature menopause might include an elevated risk of developing dementia later in life and greater age-related cognitive decline in the absence of dementia. Few studies, however, have considered these outcomes after premature menopause or have assessed long-term cognitive outcomes after surgical menopause (bilateral oophorectomy) separately from natural menopause. The latter is potentially important because surgical menopause is distinguished not only by younger age – by definition, surgical menopause is induced before the age at which natural menopause would have occurred – but also by abrupt transition and by lower levels of testosterone (derived in part after natural menopause from the ovarian stroma), in addition to low levels of estradiol, estrone, and progesterone [1].

These issues were examined by Ryan and colleagues in the population-based Three-City Study, based in the French cities of Montpellier, Bordeaux, and Dijon [2]. Women (n = 4868) were aged 65 years and older at the time of recruitment (mean age 75 years), and investigators examined cognitive outcomes in relation to age at menopause and to type of menopause (natural or surgical). Ten percent of women reported surgical menopause, and 7.6% reported a premature menopause. Well-defined procedures were in place to diagnose dementia and to detect cognitive decline. About 10.5% of 3739 women followed longitudinally developed dementia. Alzheimer's disease was not assessed separately from all-cause dementia, and analyses were not adjusted for multiple comparisons.

21 July, 2014

Bone antiresorptives, mostly bisphosphonates, are used in the treatment of metastatic bone disease from solid malignancies to reduce bone destruction, pain and skeleton-related events (SREs). Von Moos and colleagues [1] have reported pooled results from three randomized, identically designed, double-blind trials comparing subcutaneous denosumab (120 mg every 4 weeks) and intravenous zoledronic acid (4 mg/month) in patients with bone metastases from breast cancer (n = 2406), castration-resistant prostate cancer (n = 1901) or other solid tumors (n = 1597). The endpoints were pain severity, pain interference, health-related quality of life and analgesic use. Onset of moderate/severe pain was delayed by 1.8 months by denosumab treatment (hazard ratio (HR) 0.83; 95% CI 0.76–0.92; p  <  0.001) and clinically meaningful increases in overall pain interference by 2.6 months (HR 0.83; 95% CI 0.75–0.92; p <  0.001) as compared with zoledronic acid. In addition, the need for strong opioids and reduction of health-related quality of life were less common with denosumab.

Comment

Breast cancer and prostate cancer are the most prevalent malignancies in women and men, respectively. Many adjuvant treatments are associated with reproductive hormone alterations which are involved in bone mass and quality. Thus, adjuvant aromatase inhibitors and gonadotropin-releasing hormone analogues are frequently used in women with non-metastatic breast cancer. Such treatments may accelerate bone loss and increase fracture risk. In breast cancer patients with osteopenia, subcutaneous denosumab administration (twice yearly) produces significant increases in bone mineral density (BMD), both at trabecular and cortical bone, without adverse events [2]. Denosumab also increases BMD and reduces the incidence of new vertebral fractures among men under androgen-deprivation therapy for non-metastatic prostate cancer [3]. In these non-metastatic cancers, zoledronic acid has similar protective anti-osteoporotic effects as denosumab, although some related adverse effects have been reported with this bisphosphonate [4,5].

23 June, 2014: 

"the importance of the current study lies in the format of head-to-head comparison between estrogen therapy, which is the gold-standard treatment for hot flushes, and the SNRI venlafaxine hydrochloride..."

The aim of a recently published study was to determine the efficacy and tolerability of low-dose oral 17β-estradiol and low-dose venlafaxine extended release in alleviating vasomotor symptoms (VMS) [1]. In total, 339 perimenopausal and postmenopausal women (42–62 years old, mean age 55 years) with at least two bothersome VMS per day (mean 8.1 per day) were followed for 8 weeks. Participants were randomized to double-blind treatment with low-dose oral 17β-estradiol (0.5 mg/day) (n =  97), low-dose venlafaxine hydrochloride extended release (75 mg/day) (n =  96), or placebo (n =  146). Compared with baseline, the mean VMS frequency at week 8 decreased to 3.9 (95% CI 2.9–4.9) VMS per day (52.9% reduction) in the estradiol group, to 4.4 (95% CI 3.5–5.3) VMS per day (47.6% reduction) in the venlafaxine group, and to 5.5 (95% CI 4.7–6.3) VMS per day (28.6% reduction) in the placebo group. Treatment satisfaction was highest (70.3%) for estradiol, lowest (38.4%) for placebo, and intermediate (51.1%) for venlafaxine. Both interventions were well tolerated.

16 June, 2014:

The steady-state pharmacokinetics of two doses of a transdermal testosterone cream: 5 and 10 mg was investigated after daily application for 21 days by Fooladi and colleagues in a two-way, cross-over study conducted for 6 weeks [1]. Seven healthy postmenopausal women (mean age 59.3 years) were randomly allocated to 5 or 10 mg of transdermal testosterone cream applied daily to the upper arm. Serum total testosterone (TT), free testosterone (fT), sex hormone binding globulin, and metabolite concentrations were measured. Baseline-corrected and uncorrected serum TT and fT pharmacokinetic parameters (AUC0-24, Cavg, Cmax, and Tmax) were calculated using a standard model-independent approach. After the single-dose application of 5 mg of the transdermal testosterone cream on day 22, the median uncorrected TT Cavg was found to be 0.54 ng/ml (range 0.43–1.31 ng/ml), and the median uncorrected fT Cavg was found to be 4.14 pg/ml (range 2.41–9.72 pg/ml). Doubling of the dose only resulted in a 30% increase in baseline-corrected TT Cavg (0.52 vs. 0.69 ng/ml for 5 and 10 mg, respectively) and a 31% increase in baseline-corrected fT Cavg (4.75 vs. 6.24 pg/ml for 5 and 10 mg, respectively). Neither dose resulted in any meaningful variation in dihydrotestosterone, estrone, estradiol, or sex hormone binding globulin across the post-dose sampling period. It was concluded that the 5-mg dose of transdermal testosterone cream restores TT and fT levels to levels above and within the reference range, respectively, for premenopausal women. 

9 June, 2014:  

Clinical guidelines recommend the routine use of calcium and vitamin D supplementation for the prevention of fractures, especially at old age. Recent publications highlight the strong debate which has erupted in the past 5 years on the safety profile and efficacy of this treatment. I will try to put things in order for those who were not able to follow the situation more closely. In one review, Dr Weaver explains the problem [1]: 'Recently, calcium supplementation has been linked to both increased and decreased cardiovascular disease risk, creating considerable uncertainty. Moreover, recent reports have shed uncertainty over the effectiveness of calcium supplements to reduce risk of fracture.' In another review, Dr Reid took this issue further and summarized his view as follows [2]: '… findings suggest that calcium supplements have little role to play in the modern therapeutics of osteoporosis …". So what actually is going on? Are we heading for another revolution in clinical practice? What ignited the fire?

26 May, 2014

The April 16 issue of JAMA included a kind of a review on fibromyalgia, which was actually based on a conference that took place at the Medicine Grand Rounds at Beth Israel Deaconess Medical Center, Boston, Massachusetts, on October 2012 [1]. The article starts with a case history of a 64-year-old woman with ongoing, long-term, diffuse muscle pain and fatigue. Interestingly enough, the patient's testimony on how she sees her health condition was given as well. Her wish was to find a treatment regimen that would allow her to be more functional while avoiding adverse effects. The rest of the manuscript addresses the topics of diagnosis, epidemiology, pathophysiology and therapeutic options (both pharmacological and non-pharmacological). Treatment advices were: all patients should have a good therapeutic trial of a low-dose tricyclic compound; patients with co-morbid depression or fatigue should next try a serotonin norepinephrine reuptake inhibitor; non-steroidal anti-inflammatory drugs and acetaminophen can be used to treat co-morbid 'peripheral pain generators'. Complementary and alternative therapies have been less well studied but show promise. The authors also stressed the need for patient's education on the disease and counseling on the role of exercise and cognitive behavioral techniques.

19 May 2014

This trial was performed within the frame of the Austrian Study on Recurrent Venous Thromboembolism (AUREC), an ongoing prospective cohort study [1]. Between July 1992 and September 2008, consecutive patients with a first distal and/or proximal deep-vein thrombosis of the leg and/or pulmonary embolism who had been treated with anticoagulants for 3 to 18 months were included. Three weeks after withdrawal of anticoagulation, women were screened for biochemical and genetic risk factors of venous thromboembolism (VTE). The present prospective analysis included data collected until March 2012. The cohort was composed of 630 women (333 estrogen users, 297 non-users, average age 46 ± 17 years) with a first VTE who were followed for an average of 69 months after anticoagulation withdrawal. Excluded were women with a previous or secondary VTE; coagulation inhibitor deficiency; lupus anticoagulant; cancer; pregnancy; requirement of long-term antithrombotic therapy; or homozygosity or double heterozygosity for factor V Leiden and/or the G20210A prothrombin mutation. The endpoint was objectively documented symptomatic recurrent VTE. VTE recurred in 22 (7%) estrogen users and in 49 (17%) non-users. After 1, 2 and 5 years, the cumulative probability of recurrence was 1% (95% confidence interval (CI) 0–2), 1% (95% CI 0–2) and 6% (95% CI 3–9) among estrogen users and 5% (95% CI 2–7), 9% (95% CI 6–13) and 17% (95% CI 12–22) among non-users. Compared to non-users, estrogen users had an adjusted relative risk (RR) of recurrent VTE of 0.4 (95% CI 0.2–0.8). Compared to non-users in the respective age groups, the RR of recurrence was 0.4 (95% CI 0.2–0.8) among estrogen-containing contraceptive users and 0.7 (95% CI 0.3–1.5) among women using estrogen-containing menopausal hormone therapy. The study conclusions were therefore that women who had their first VTE while using estrogens have a low risk of recurrent VTE. These women might not benefit from extended anticoagulant therapy.

28 April, 2014

In all fields of medicine, we, the health-care providers, witness a growing number of patients who use all sorts of complementary and traditional medicine (CAM). A new study, which was published in a journal with which most of us are not familiar, compared the results from two surveys done in two geographically and culturally diverse sites (Sydney and Bologna) to examine factors that determine the extent and pattern of CAM use to alleviate menopausal symptoms [1].

Women, aged 45–65 years, who were symptomatic when transitioning through menopause or asymptomatic but taking menopause-specific treatments, were recruited in Sydney (n = 1296) and Bologna (n = 1106) to complete the same voluntary, anonymous, and self-administered questionnaire. Demographics of the two cohorts differed significantly. CAM was more popular in Sydney.

The most significant determinants of CAM consumption were the use of CAM for other conditions besides menopause and the severity of vasomotor symptoms. Occupational status was a determinant of CAM use amongst Bologna respondents only.

In order to relieve symptoms, Australian and Italian women used different CAM modalities whose effectiveness was generally perceived as good. In general, CAM use was popular amongst menopausal women from Sydney and Bologna. Differences in the patterns of CAM use seem to depend on CAM availability and on the educational level and professional status of users. The complex interaction between market, social, and cultural factors of CAM use seems to be more influential on women's choice of CAM than the available evidence of their effectiveness.

14 April, 2014

In a recent publication, under the section heading 'Personal Perspectives', Dr James Simon considers hypothetical comparisons between oral conjugated equine estrogens (CEE) and transdermal estradiol and between oral medroxyprogesterone acetate (MPA) and oral micronized progesterone for their effects on four primary outcomes of the Women's Health Initiative (WHI) [1]: cardiovascular disease risk, cerebrovascular disease risk, venous thromboembolism risk, and breast cancer risk. Although the discussion in this article focused on transdermal estradiol delivered through patches, gels, or lotions, it could be broadened to include all forms of non-oral estrogen administration. After a brief review of the WHI and a survey of the relevant literature in which the safety of these various hormone therapies was assessed or compared, the author used statistical methods to ascertain the attributable risk of venous thromboembolism for transdermal estradiol versus oral hormone therapy and imputed those risks into the WHI primary outcomes.

Comment

This is not a regular comment for Menopause Live, but rather an appraisal. Although medicine is not accurate as mathematics is, it cannot be based on a 'what if' situation, since the treating physician makes decisions after considering both the individual clinical facts and personal experience. Still, the 'what if' issue here is not purely fiction, but an attempt to extrapolate results from studies in women using transdermal estradiol and progesterone to the WHI arena, where CEE and MPA were the only study medications. The manuscript is built in a very logical way, first bringing the up-to-date information on all available aspects of the WHI study results, then discussing the four risk domains mentioned earlier in regard to current knowledge on the potential relevant adverse effects of non-oral estradiol and progesterone, and finally bringing the author's conclusions. The main message, which is not innovative, but well phrased and referenced, is that 'postmenopausal hormones' should not be regarded as a single entity, and therefore the WHI results should not be the sole basis for guidelines and recommendations.

10 March, 2014

The potential association of postmenopausal hormone use and the occurrence of acute pancreatitis was investigated in a prospective study involving 31,494 postmenopausal women (aged 48–8 years) from the population-based Swedish Mammography Cohort [1]. Participants completed a baseline questionnaire in 1997 assessing their use of hormone replacement therapy (HRT). The cohort was linked to the hospital-based Swedish National Patient Register to determine hospital admissions for acute pancreatitis through 2010. Over a total follow-up of 389,456 person-years, 237 cases of incident acute pancreatitis were identified. The age-standardized incidence rates per 100,000 person-years were 71 cases among women who had ever used HRT and 52 cases among women who had never used such hormones. Among ever-users of HRT, the multivariable-adjusted relative risk (RR) of acute pancreatitis was 1.57 (95% confidence interval (CI) 1.20–2.05) compared with never-users. The risk did not differ by current or past use, but it seemed to be higher among women who used systemic therapy (RR = 1.92, 95% CI 1.38–2.66) and among those with duration of therapy of more than 10 years (RR = 1.87, 95% CI 1.11–3.17).

Comment

So let's be realistic. Should this information change our perceptions on the risk of HRT? Does it have any innovative clinical significance? On the one hand, it is a large-scale study, with a long follow-up period. On the other hand, data on hormone use was self-reported and did not include important information on specific hormonal preparations, dose and route of administration of HRT [1]. By the end of the day, there were 19 additional events of acute pancreatitis among 100,000 person-years, or only about two additional cases among 10,000 women per year of use. This seems to be a tiny risk that may not be accounted for when benefit–risk balance of HRT is discussed. Furthermore, no data were presented for the exact definition and severity of acute pancreatitis, i.e. whether a mild course of abdominal pain with elevation of liver enzymes/amylase serum levels, or a serious disease necessitating surgical procedures, or even a fatal outcome, etc. Nevertheless, the authors concluded that 'Physicians should consider this potential increase in risk when prescribing such therapy.'