12 January, 2015

A new article reviews the effects of age-related hormone decline on the aging process and age-related diseases such as sarcopenia and falls, osteoporosis, cognitive decline, mood disorders, cardiovascular health and sexual activity [1]. Information on the efficiency and safety of hormone replacement protocols in aging patients is provided as well. Anti-aging therapies are a huge business world-wide, and this reflects a human desire to fight nature and prolong longevity. During the last 20 years, a multitude of anti-aging practices have appeared, aiming at retarding or even stopping and reversing the effects of aging on the human body. One of the cornerstones of anti-aging is hormone replacement. Women live one-third of their lives in a state of sex hormone deficiency, whereas men are also subject to age-related testosterone decline, but andropause remains frequently under-diagnosed and under-treated. Due to the decline of hormone production from the gonads in both sexes, the importance of dehydroepiandrosterone (DHEA) in steroid hormone production increases with age. However, DHEA levels also decrease with age. Also, the age-associated decrease in growth hormone may be so important that insulin growth factor-1 levels found in elderly individuals are sometimes as low as those encountered in adult patients with established deficiency. Skin aging, as well as decreases in lean body mass, bone mineral density, sexual desire and erectile function, intellectual activity and mood have all been related to this decrease of hormone production with age. Great disparities exist between recommendations from scientific societies and the actual use of hormone supplements in aging and elderly patients.

Comment

Before getting into the heart of the matter, one must define several key parameters. Brüssow gives the accepted definitions of health, aging and healthy aging [2]. Health, according to the 1948 WHO definition, is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity. Aging is a progressive decline in structure and function of the body, or regression of physiological function accompanied by advancement of age. The definition in the Nurses' Health Study for successful aging was as follows: being free from 11 major chronic diseases (such as cancer, cardiovascular, pulmonary, renal, Parkinson’s disease), no cognitive impairment, no physical disabilities, no mental health limitations [3]. The pivotal physiological change throughout the perimenopause is the decline in estrogen and progesterone production, whereas an abrupt, substantial decrease in all sex hormone levels follows castration. This creates a significant deficiency state to which the body must adapt. The associated metabolic alterations may therefore be regarded as induced by the menopause but, in fact, in most cases the effects of aging itself are the main underlying factors. Nevertheless, it has always been tempting to believe that treating menopausal women with estrogen replacement will change the hormonal milieu, correct the deprivation state and reverse not only the menopause-related but also the age-related physiological processes. This is very logical, but does this work in real life?

8 December 2014

A recent review written by three Finnish psychiatrists supports the use of estrogens, perhaps together with antidepressants, for depression and anxiety in perimenopausal women [1]. Depressive symptoms are experienced by 15–50% of women during the menopausal transition and up to 30% of perimenopausal depression is severe enough to be regarded as a depressive disorder. This problem, described as 'reproductive depression' [2] occurs with fluctuations of gonadal hormones in the form of premenstrual depression, postnatal depression and climacteric depression. In the menopausal age group, the depression, anxiety and loss of self-confidence are at their worst in the 2–3 years of the transition period before the cessation of periods. Toffol and colleagues, in their review of the literature, have come to the conclusion that hormone therapy may contribute to the alleviation of menopause-related depressive symptoms. They claim that the administration can be followed across time and should be specifically individualized. In cases of more severe depressive disorders, a combination of antidepressants and hormone therapy should be considered. This view has also been proposed by others [3,4].

Comment

The perimenopause is usually accompanied by more-or-less-impairing climacteric symptoms of hot flushes, palpitations and tachycardia as well as some degree of psychological symptoms of sleep impairment, anxiety, panic attacks and depressive symptoms. The proportion of perimenopausal women suffering depressive symptoms ranges between 15% and 50%. It is possible that the fluctuations in estrogen levels and their eventual fall increase the risk in women who are vulnerable. These are particularly women who have had a premorbid history of psychiatric problems, particularly anxiety and depression related to reproductive events such as menstruation, post pregnancy and the contraceptive pill.

The cause of this hormone-responsive depression is unclear but, in our present state of knowledge, it is certain that gonadal hormones produce many effects on the central nervous system. In the adult brain, estrogen and progestogen receptors are widely expressed in different regions. Estrogen receptors are present not only in the hypothalamus but also in the hippocampus, amygdala, cerebellum, pituitary, cerebral cortex and glial cells. The mechanism is even more complex in that there are different types of estrogen receptors which are expressed in different brain regions and in different cells within the same brain region and even in the same cell in the same region. Therefore, the final effects induced by estrogens change depending on the type of receptor to which they bind. Target genes include those responsible for neurotransmitters, serotonin and GABA. The role of progesterone is even more complicated as it is involved in the control of opioidergic, sertoninergic and cholinergic systems with anxiolytic effects.

17 November, 2014

The effects of hormone therapy (HT) on mean and visit-to-visit variability (VVV) of blood pressure in postmenopausal women were recorded in the Women's Health Initiative (WHI) randomized controlled trials [1]. Blood pressure was measured at baseline and annually in the two WHI HT trials, in which 10,739 and 16, 608 postmenopausal women were randomized to conjugated equine estrogens (CEE, 0.625  mg/day) or placebo, and CEE plus medroxyprogesterone acetate (MPA, 2.5  mg/day) or placebo, respectively. At the first annual visit (year 1), the mean systolic blood pressure was 1.04  mmHg (95% confidence interval (CI) 0.58–1.50) and 1.35  mmHg (95% CI 0.99–1.72) higher in the CEE and CEE + MPA arms, respectively, compared with the mean systolic blood pressure in women taking the corresponding placebos. These effects remained stable after year 1. CEE also increased the VVV of systolic blood pressure (ratio of VVV in CEE vs. placebo, 1.03; p  <  0.001), whereas CEE + MPA did not (ratio of VVV in CEE + MPA vs. placebo, 1.01; p  =  0.20). After accounting for study drug adherence, the effects of CEE and CEE + MPA on mean systolic blood pressure increased at year 1, and the differences in the CEE and CEE + MPA arms vs. placebos also continued to increase after year 1. Further, both CEE and CEE + MPA significantly increased the VVV of systolic blood pressure (ratio of VVV in CEE vs. placebo, 1.04; p  <  0.001; ratio of VVV in CEE + MPA vs. placebo, 1.05; p  <  0.001).

Comment

It is well documented that elevated blood pressure in women is an important risk factor for cardiovascular disease and therefore its control may have a substantial impact on women's health [2,3]. Shimbo and colleagues [1] concluded that, in the particular clinical set-up of the WHI trial (women at a mean age of 62 years using CEE or CEE + MPA at conventional doses), mean and VVV of systolic blood pressure were increased. Thus, these results actually support the WHI-related notion that HT may have a detrimental effect on coronary artery disease. Although the exact mechanisms that may explain how HT influences blood pressure are not fully understood, several possibilities have been suggested [4]. HT has an effect on vascular tone, cardiac function, the immune system, the kidneys and other organs. Of particular interest is the modulation of the renin–angiotensin pathway by estrogen.

10 November, 2014

One of the main arguments against extrapolation of the Women's Health Initiative (WHI) study data to the whole postmenopausal population was that it actually focused on the 60+ year-old women who were treatment-naïve until then [1], whereas in real life most hormone users are 45–55 years old at initiation of therapy. The Kronos Early Estrogen Prevention Study (KEEPS) was designed to provide information on the effects of hormone therapy (HT) in recently menopausal women. Results from KEEPS are now published in the literature [2]. The main aim of KEEPS was to assess atherosclerosis progression and cardiovascular risk factors after HT initiation. The study enrolled 727 healthy menopausal women aged 42–58 years (mean 52.7 years), between 6 and 36 months from last menses, without prior cardiovascular disease events, who had a coronary artery calcium (CAC) score less than 50 Agatston units and had not received estrogen or lipid-lowering therapy for at least 90 days. Study medications included oral conjugated equine estrogens (o-CEE), 0.45 mg/day, or transdermal 17β-estradiol (t-E2), 50 μg/day, each with 200 mg of oral progesterone for 12 days per month, or placebo for 48 months.

The primary endpoint was annual change in carotid artery intima-media thickness (CIMT). Secondary endpoints included changes in markers of cardiovascular disease risk. Of 727 randomly assigned women, 89.3% had at least one follow-up CIMT and 79.8% had CIMT at 48 months. Mean CIMT increases of 0.007 mm/year were similar across groups. The percentages of participants in whom the CAC score increased did not differ significantly across groups. No changes in blood pressure were observed with o-CEE or t-E2. Low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol levels improved and levels of C-reactive protein and sex hormone binding globulin but not interleukin-6 increased with o-CEE. Insulin resistance decreased with t-E2. Serious adverse events did not differ by treatment. Power to compare clinical events was insufficient. Thus 4 years of early HT did not affect progression of atherosclerosis despite improving some markers of cardiovascular disease risk.

06 October, 2014:

With aging, women's bodies undergo changes that can affect body image perception, yet little is known about body image in midlife. In a subset of the SWAN cohort from Chicago, the associations between body image and depressive symptoms were investigated [1]. Body image was measured using the Stunkard Adult Female Figure Rating Scale, and a clinically significant level of depressive symptoms was defined as a Center for Epidemiologic Studies Depression Scale (CES-D) score of ≥ 16 (total n = 405; depression n = 63 (15.6%)). Differences between perceived actual, perceived ideal and actual body size and responses to questions concerning weight satisfaction and attractiveness were examined using logistic regression for associations with a CES-D score of ≥ 16. Women with body image dissatisfaction (odds ratio, OR = 1.91; p = 0.04) or who perceived themselves as 'unattractive' (OR 7.74; p < 0.01) had higher odds of CES-D of ≥ 16. There was no significant difference by race, and results were not confounded by body mass index. To conclude, midlife women with poor body image may be more likely to have clinically significant levels of depressive symptoms.

29 September, 2014: 

Urinary incontinence (UI) is a common and frequently overlooked problem in aging women [1,2]. Leaking urine limits daily and working activities, social interaction and sexual intimacy, and therefore severely disrupts quality of life [3]. The relationship between menopause, aging and hysterectomy is complex and still unresolved. While it is clinically appreciated that all these factors have some impact on the frequency and severity of urinary incontinence, epidemiologic evidence is contradictory and a clear demonstration of how these factors interact in favoring incontinence is not available.

Removal of the uterus is one of the most frequent surgical procedures performed in women, and appropriate counseling related to future risks, particularly that of UI or pelvic organ prolapse (POP), is currently based on feeble evidence.

The Women’s Health Initiative Observational Study (WHI OS) has explored this issue, assessing prevalence, at baseline and after a 3-year time interval, of different forms of UI in 92,093 postmenopausal women between 50 and 80 years (53,569 with the uterus in place, 38,524 hysterectomized) [4]. This is the largest cohort of women in which information on UI has ever been gathered.

22 September, 2014 

In their recent review, Hardman and Gebbie provide a great service to colleagues who face questions on the need for contraception in the perimenopause [1]. The manuscript is very practical, giving a little background and mainly focusing on various options for contraception, and their advantages or side-effects. The authors also present an algorithm for a multitude of perimenopausal situations. Here is the review Abstract:

'Perimenopausal women have low fertility but must still be advised to use contraception until natural sterility is reached if they are sexually active. Patterns of contraceptive use vary in different countries world-wide. Long-acting, reversible contraceptive methods offer reliable contraception that may be an alternative to sterilization. Hormonal methods confer significant non-contraceptive benefits, and each individual woman should weigh up the benefits and risks of a particular method. No method of contraception is contraindicated by age alone, although combined hormonal contraception and injectable progestogens are not recommended for women over the age of 50 years. The intrauterine system has particular advantages as a low-dose method of effective hormonal contraception, which also offers control of menstrual dysfunction and endometrial protection in women requiring estrogen replacement. Condoms are recommended for personal protection against sexually transmitted infections in new relationships. Standard hormone replacement therapy is not a method of contraception.'

Comment

The main question to answer is, 'When can a perimenopausal woman stop taking contraception'. The authors, correctly, state that a spontaneous pregnancy in women over 50 years old is rare. They also explain the UK principles for perimenopausal contraception. I believe that the limit at which to discontinue the progestogen-only pill, barrier methods or non-hormonal intrauterine device of 55 years is rather high. My advice is to stop using these methods already at the age of 52 years, but it is certainly a matter of personal opinion.

From 2007 to 2010, an average of 281,406,600 medical visits occurred annually in the USA according to data from medical records of national representative visits to office-based physicians and visits to outpatient departments. The current study analyzed 63 million preventive care visits, of which 44% were visits to OB/GYNs and 56% were to primary-care doctors [1]. Women 50 years or older had a higher percentage of preventive care visits to general practitioners (GPs) than younger women: for age 30–49 years, 55% of women saw OB/GYNs vs. 45% who saw GPs; for age 50–64 years, 38% vs. 63%; and for > 65 years old, 19% vs. 81%, respectively (p < 0.001). The OB/GYN visits focused predominantly on reproductive health-related services, whereas visits to GPs provided a wider range of services and higher volume of counseling, even among women of child-bearing age. Women who saw OB/GYNs were more likely to get screened for cervical and breast cancers, Chlamydia and osteoporosis, compared to those who went to primary-care doctors. Contrarily, those who went to primary-care doctors were more likely to get screened for colon cancer, high cholesterol and diabetes and to be counseled about diet, exercise and obesity. To note that the majority of the total medical visits (about 82% of visits to OB/GYNs and 74% of visits to GPs) did not report on counseling. Because physicians have had little to no incentive in most payment systems to document counseling performed during clinic appointments, counseling services may have been underestimated.

Comment

The results of the above study clearly point at a known and rational fact that gynecologists limit their engagement with preventive medicine to OB/GYN-relevant issues during consultations. Because young to midlife women tend to visit OB/GYNs more often than GPs, it seems necessary to preach for a more active involvement of OB/GYNs in a wider range of preventive measures. Preventive medicine for middle-aged women has been one of the main educational goals of the International Menopause Society (IMS), as expressed in the latest version of the IMS recommendations on menopausal hormone therapy and preventive strategies for midlife health [2]. Commitment of OB/GYNs to discuss preventive medicine with their patients should be based on two components. The first is obtaining the knowhow on what to do and how to implement it in routine clinical work. Various relevant guidelines and recommendations probably make this easier. The second is the compensation any physician should receive for giving time to discuss these issues with his/her patients. If this factor is not properly settled with the health maintenance organizations, the incentive to do it will obviously be low. Nevertheless, the IMS believes that being a menopause specialist dictates a more holistic approach. Although most IMS members are either OB/GYNs or reproductive endocrinologists, they should integrate their traditional role in the field of gynecology into another mode of operation that includes screening and counselling menopausal women on prevention of the chronic diseases of aging.

18 August, 2014

Ovarian conservation at the time of hysterectomy for benign disease has certainly become more common, mainly as the result of the landmark paper of Parker and colleagues [1]. This was a focal point in the beginning of a turnaround in the thinking of many clinicians. Now a new body of work examining a portion of this argument comes from the Cancer Prevention Study-II Nutrition Cohort published in Obstetrics & Gynecology by Gaudet and colleagues [2].

It was a fairly straightforward cohort study involving over 66,000 postmenopausal women. In a median follow-up of just under 14 years, 8621 cancers were diagnosed (12.9% of the cohort). The authors compared hysterectomy with BSO at any age (1892 cases) with no hysterectomy (5586 cases) and found a statistically significant 10% reduction in all cancers. However, if the surgery was performed at age 55 or older, there was no reduction in overall cancer, yet hysterectomy with BSO at any age resulted in a 20% reduction in breast cancer that was statistically significant.

Finally, hysterectomy without BSO if performed in women at age 45 or younger, was associated with a 12% decrease in all cancer, and, at any age, with a 14% decrease in breast cancer, both of which were statistically significant. The authors concluded that this information should be used in counseling women undergoing hysterectomy.

11 August, 2014

Chronic pharmacologic treatments have the risk of low adherence and persistence which depend on the disease severity, preventive objectives, co-morbidity, other concurrent medications (polymedication) and adverse events. Wade and colleagues [1] reported follow-up data regarding osteoporosis medication persistence and switching at 24 months and 36 months in postmenopausal women from the cohort of the US Prospective Observational Scientific Study Investigating Bone Loss Experience (POSSIBLE). Postmenopausal women (n = 3011) were enrolled by 134 primary-care physicians who were considered to be the top 40% prescribers of osteoporosis medications in 2003. Medications initially prescribed were oral bisphosphonates (alendronate, risedronate, or ibandronate), oral or transdermal postmenopausal estrogen (PME), parathyroid hormone, calcitonin, raloxifene, or a non-prescription agent (calcium and/or vitamin D supplement).