31 August, 2015:

Vulvovaginal atrophy (VVA) is a major consequence of menopause and related loss of the estrogenic effect on the vaginal epithelium. For many decades, the ideal therapeutic approach was to use systemic estrogen, which was very effective. Local treatment with vaginal estrogen (creams, tablets, and rings) is effective to the same extent. But, on the other hand, the downside of systemic hormone therapy (risks for breast cancer, cardiovascular and thromboembolic events, perhaps some cognitive decline) became a major issue after the first release of data from the Women's Health Initiative (WHI) trial in 2002, and changed both patients' preferences and prescription habits. The uncertainty about estrogen resulted in two changes concerning the treatment of VVA. The first has been to lower the dosage of local estrogen preparations, still maintaining a good clinical response and symptom relief, but keeping serum estrogen levels well below premenopausal levels. The other was to promote non-estrogenic and non-hormonal therapies, either by using marketed products, or by developing new drug formulations. Among the recently approved medications is prasterone – an intravaginal DHEA preparation [1,2]. In a 52-week-long study which showed a significant improvement in vaginal dryness and irritation/itching, and in pain during sexual activity, the authors commented that 'The treatments currently used against VVA are essentially intravaginal and oral estrogen; however, as indicated by the black box on the estrogen information leaflets, there are risks. In fact, even at the lowest dose and dosing regimen, all intravaginal estrogen preparations increase serum estrogens above the normal postmenopausal range or above the threshold of no biological activity with the accompanying risk of systemic effects' [2]. Is this statement supported by hard clinical data?

24 August, 2015

Breast cancer can occur in women below 50 years old and represents 25% of the total number of cases. Risk factors and histological characteristics of breast cancer are different in young women compared with older women. There are many publications on the risk of breast cancer and hormone treatment (MHT) in postmenopausal women. However, less is known about use of MHT in young women and especially looking separately at the impact of estrogen-only treatment (ET) and combined estrogen–progestin treatment (EPT). A recent study aimed to investigate whether the use of MHT is a risk factor for young-onset breast cancer [1]. The authors used the Two Sister Study for this purpose. It is a sister-matched case–control study of young-onset breast cancer from the Sister Study, a prospective cohort study of 50,884 women without breast cancer who had a full or half sister who had been diagnosed with breast cancer; 1422 cases and 1689 controls were included. Because 10% of control sisters and no case sisters had reached the age of 50 years before 2002 when the WHI study was published and because MHT prescriptions decreased drastically thereafter, a propensity score was used to decrease the impact of this bias. Results show that a low percentage of women used MHT. The most frequent was ET (7% of controls and 4% of cases), then EPT (3% and 2%, respectively) and progestin alone (PT) (1% and 1%). Crude odds ratios (OR) for breast cancer were less than 1 for every MHT category except PT. ET use was inversely associated with young-onset breast cancer (propensity score, adjusted OR =0.58; 95% CI 0.34–0.99); the adjusted OR for EPT use was 0.80 (95% CI 0.41–1.59) and for PT was 1.51 (95% CI 0.76–3.00). Adjustment for duration of use, age at first use, menopausal status at first use, and recency of use did not appear to modify the association. There was no interaction by oophorectomy status but women using ET were more often hysterectomized and oophorectomized. The authors concluded that neither ET nor EPT increase the risk of young-onset breast cancer and that ET might be associated with a reduced risk.

17 August, 2015

In contrast to the large body of literature on psychological symptoms during the menopause transition, relatively little is known about positive well-being including happiness, satisfaction with life and self-actualization at this time. Our recent review article 'Positive well-being during the menopausal transition' [1] responded to this issue though synthesizing quantitative work on positive functioning across the menopause transition. Nineteen relevant studies were identified, and the vast majority found that both menopausal stage and the presence/frequency of vasomotor symptoms were independent of positive well-being. Four studies using aggregate scales of menopausal symptoms such as the Greene Climacteric Scale (GCS), however, demonstrated that symptoms were strong predictors of diminished well-being. These findings demonstrate the importance of delineating menopausal factors in order to clearly determine which aspects of menopause are most likely to have an impact on positive well-being.

20 July, 2015 

Most women experience menopause between the ages of 45 and 55 years. However, 5% of women will go through menopause early, between the ages of 40 and 45 years, and 1% of women become menopausal prematurely, before the age of 40 years [1]. The causes of premature or early menopause are multiple and range from the most common, bilateral oophorectomy, to more rare causes such as genetic, autoimmune, or infectious etiologies. There are multiple adverse long-term health consequences associated with premature or early menopause, including increased risk of dementia, parkinsonism, glaucoma, depression, anxiety, osteoporosis, coronary heart disease, heart failure, sexual dysfunction, and early death. Replacing estrogen mitigates some of these risks, although it may not completely protect against the increased risk of parkinsonism, glaucoma, mood disorders, and sexual dysfunction [1].

Comment

The ovaries are both reproductive and endocrine organs. They secrete hormones both before menopause (primarily estrogen, progesterone, and testosterone) and after (primarily testosterone, androstenedione, and dehydroepiandrosterone). Ovarian hormones have important reproductive actions; however, they also have important endocrine actions mediated by receptors spread throughout most tissues and organs of the body [2]. Removal of the ovaries reduces the risk of ovarian (by 80–90%) and breast (by 50–60%) cancer; however, it increases the risk of all-cause mortality (28%), lung cancer (45%), coronary heart disease (33%), stroke (62%), cognitive impairment (60%), parkinsonism (80%), psychiatric symptoms (50–130%), osteoporosis and bone fractures (50%), and impaired sexual function (40–110%). The magnitude of the risk varies depending on the study referenced, the age at the time of oophorectomy, and the use of estrogen therapy after the surgery [2].

30 May, 2016: 

The relationship between menopause, paid employment and workplace environments is under the spotlight with the review of existing studies presented in our multi-authored paper [1]. 

We report that since 2000 there has been a growing number of studies which have systematically explored two interrelated concerns: whether, to what extent, and how menopausal symptoms influence women's work, including costs to employers; and the role of physical and psychosocial aspects of the workplace environment in aggravating or alleviating symptoms.

Work factors as well as menopause-related symptoms and disease affect working women. Work stress/overload, long/inflexible working hours, perceived job control, and gendered/aged-based workplace norms and stigmas, and anticipated supervisor/collegial responses, are key psychosocial factors that compound and complicate the impact of women's symptom experience. Vasomotor symptoms (VMS) are often reported as having a negative effect on women's productivity and experience at work. In some studies, the psychological and somatic symptoms accompanying VMS are more significant than the hot flashes per se.

Suggestions for employers are made which would support working women through menopause and the years that follow. Changes which could be made in the workplace are recommended, including health promotion programs.

29 June 2015

Peter Schmidt and his team have published some much needed research comparing the effects of the withdrawal of estrogen from women who have perimenopausal depression (PMD) with those who have continued the therapy [1]. After 3 weeks of open-label administration of transdermal estradiol (100 µg/day), participants were randomized to a parallel design to receive either estradiol (100 µg/day; 27 participants) or matched placebo skin patches (29 participants) for 3 additional weeks under double-blind conditions. The women completed the Center for Epidemiologic Studies-Depression Scale, the 17-item Hamilton Depression Rating Scale (completed by raters blinded to diagnosis and randomization status), and self-administered visual analog symptom ratings, and blood hormone levels were obtained at weekly clinic visits. The results showed that none of the 29 patients who received estradiol reported depressive symptoms but those who crossed over from estradiol to placebo experienced a significant increase in depressive symptoms. The conclusion was that, in women with a past history of PMD who had previous responded to hormone therapy, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that changes in estradiol can trigger an abnormal behavioral state in these susceptible women. Women with a history of PMD should be alert to the risk of recurrent depression when discontinuing hormone therapy and psychiatrists should be aware that there is more appropriate treatment than antidepressants and mood stabilizing drugs.

22 June 2015: 

As a clinician, I was not aware of the growing interest in analyzing urine proteomics. The routine urine analysis includes urine protein levels but, in fact, in almost all cases we are interested in the urine albumin as a marker of kidney disease (nephropathy of all sorts, mainly diabetic). A full screen of urinary proteins and peptides (the urine proteome) is not available for routine clinical work. The reason for this has been two-fold: lack of data to establish the value of the test, and technical issues related to preparing the samples for the best and most accurate analysis. However, many recent studies show that characteristic changes in healthy elderly people's urine proteomes appear to reflect certain physiological processes associated with metabolic changes and the aging process [1]. Furthermore, documenting the urine proteome may facilitate earlier detection of disease, improve assessment of prognosis and allow closer monitoring of response to therapy [2]. So, which of the urinary proteins may serve as biomarkers of specific diseases?

18 May, 2015:

The average age of menopause in women in the Western world is 51 years. Women who experience menopause between the ages of 40 and 45 years have what has been called 'early menopause', which is reported to occur in approximately 5% of women [1, 2]. These women, with a premature decrease of estrogen production, seem to have an increased risk of overall mortality and morbidity [2–5]. However, to our knowledge, only a few studies have been published on the benefits from long-term hormone therapy (HT) in this population [4,6].

According to the standard recommendations, HT should be given to women at premature or early menopause and should be continued at least to age 51–52 years, the average age of menopause in Shuster's study population (Mayo Clinic Olmsted County, Minnesota) [2].

In Sweden, the use of HT in 47–56-year-old women was approximately 6% (data from the Swedish Prescribed Drug Registry 2010–2012), which we consider to be an underutilization of HT when considering the prevalence of symptoms in this age group. We also suspected that the underutilization would be even more pronounced in women aged 40–44 years.

The aim was to determine the number of current and new HT users and the duration of HT use in Swedish women aged 40–44 years with probable early menopause during a 5-year period (July 2005–December 2011).

11 May, 2015:

There is a biological plausibility for the association between sexual desire and androgens. Indeed, according to epidemiological and clinical studies, they both decline with age. However, any attempt to link directly low sexual desire with circulating low androgens (total testosterone, free testosterone) or androgen precursors (androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)) has failed to identify a lower limit that can be used to diagnose women with sexual dysfunction related to androgen deficiency [1]. A Danish cross-sectional study by Wåhlin-Jacobsen and colleagues [2] has recently reported that sexual desire, measured by the total score in the sexual desire domain of the Female Sexual Function Index (FSFI), correlated overall with free testosterone and androstenedione in a cohort of 560 healthy women aged 19–65 years. Moreover, the androstenedione : total testosterone ratio, an indirect marker of the activity of 17β-hydroxysteroid dehydrogenase, was overall correlated with women's sexual desire in women not using systemic hormonal contraception (HC) or postmenopausal hormone therapy (HT), indicating that the speed of transformation of androstenedione to testosterone is important. When the study population was stratified into three age groups depending on the intake of HC and HT, the authors demonstrated that, in women aged 25–44 years with no use of HC, sexual desire correlated with total testosterone, free testosterone, androstenedione, and DHEAS, whereas, in women aged 45–65 years, only androstenedione correlated with sexual desire. The primary androgen metabolite androsterone glucuronide did not show a correlation with sexual desire.

21 April, 2015

The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis was examined by Black and colleagues in a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT) [1]. The first extension study (EXT1) with zoledronic acid 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), a decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers compared with discontinuation after 3 years, but left the optimal duration of treatment uncertain.

To investigate the longer-term efficacy and safety of zoledronic acid, a second extension (EXT2) was conducted to 9 years, in which 190 women, out of 451 women on zoledronic acid for 6 years in EXT1, were randomized to either zoledronic acid (Z9) (n = 95) or placebo (Z6P3) (n = 95) for three additional years. The primary endpoint was the change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Secondary endpoints included fractures, bone turnover markers, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% CI -0.37% to 1.93%; p = 0.183). Bone turnover markers showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest that almost all patients who have received six annual infusions of zoledronic acid can stop medication for up to 3 years with apparent maintenance of benefits.