Reprint of The nature and utility of the phytoestrogens: a review of the evidence.

Non-prescription remedies are becoming increasingly popular particularly amongst postmenopausal who in this market are the largest consumers. Phytoestrogens are a large family of plant derived molecules possessing various degrees oestrogen like activity. Food or food supplements containing phytoestrogen are often been advocated as an alternative to hormonal replacement therapy (HRT) in women with contraindications to the use of conventional oestrogen replacement, or simply wanting a more 'natural' alternatives. There have been several studies performed with phytoestrogen in various aspects of the postmenopausal women health. Results have been sometimes conflicting and difficult to interpret. The lack of knowledge of what precisely is the active ingredient, its minimally effective doses, the lack of standardisation of the preparations used as well as the large individual variability of metabolism of precursors introduced with the diet may all have played a role in confusing the issue about effectiveness of these compounds. Phytoestrogen fall in the gray area between food and drugs hence in spite of the vast public interest, there are no interests in company producing these supplements in investing in research from which they will not exclusively benefit from. It is difficult for the physician to know how to advise patients on this matter. In this paper we critically review the clinical data available to date in an attempt to answer some of the most commonly asked questions about dose and type of phytoestrogens supplementation most likely to be effective in different aspects of climacteric woman health.

Bone mineral density and depot medroxyprogesterone acetate.

INTRODUCTION: Depot medroxyprogesterone acetate (DMPA) suppresses pituitary gonadotrophin output, thus, suppressing ovulation. Estrogen production from the ovary is also strongly inhibited, and the resulting estrogen deficiency has a detrimental impact on bone. Depot medroxyprogesterone acetate may be particularly detrimental in young women, as it may impede attainment of peak bone mass, and switching to a different contraceptive is recommended. However, the effect of sequential use of DMPA with other contraceptives in this age group has not been investigated. METHODS: This was a cross-sectional analysis of 218 DMPA users who were 20 years or older (mean, 31 years, +/-8.9 SD) at the time of bone mineral density (BMD) estimation. The majority of women had used one or more contraceptive beside DMPA. The most commonly used alternative contraceptive was the oral combined pill (OCP). It was used by 65% of women (n=143) and for an average duration of 6 years. A logistic regression model was used to estimate the association between potential risk factors and low bone mass. RESULTS: The prevalence of low bone mass at either hip or spine (T< or =1) was 41%. The prevalence of a T score below -2.5 was 5%, and 45% of women had already sustained one fracture. Younger age was associated with higher BMD [odds ratios (ORs), 0.054; 95% confidence interval (CI), 0.007-0.431]. However, this protective effect of age was lost once the interaction between the duration of both DMPA and OCP was introduced into the model (OR for low BMD, 1.42; 95% CI, 1.09-1.8). The use of DMPA first before ever use of OCP was particularly detrimental to BMD (OR, 3.94; 95% CI, 1.08-14.0). On the contrary, body mass index was positively associated with BMD (OR, 0.86; 95% CI, 0.8-0.9). No other demographic or anamnestic variables significantly predicted the presence of low BMD in this group of young women. This group of DMPA users appear to be at a very high risk of both low BMD and fractures, possibly independently of DMPA use. This needs to be considered when writing guidelines for risk assessment. CONCLUSION: The use of DMPA before achievement of peak bone mass may be particularly detrimental to bone, but switching DMPA with the OCP in these women does not seem to confer specific benefit in terms of bone density. This needs to be taken into consideration when a change in contraceptive is considered purely for the sake of bone protection.

Noradrenergic and serotonergic modulation to treat vasomotor symptoms.

Hot flushes are a major clinical problem for many menopausal women. Their aetiology is unknown. Centrally acting neurotransmitters are involved, but this involvement is yet to be fully characterized. In clinical trials with optimal patient selection and compliance, estrogen can reduce the frequency of hot flushes by 70-80%, and placebo by 20-40%. For some women, however, there are contraindications to the use of estrogen, and others are unwilling to use it. Furthermore, hot flushes may persist in spite of adequate estrogen replacement, and to improve symptoms physicians then have either to add another drug to the regimen or find an alternative to estrogen. The most commonly used non-hormonal alternatives for climacteric symptoms are neurotransmitter modulators such as the selective serotonin reuptake inhibitors. These reduce the frequency of hot flushes by 60%. The mechanism of this effect appears to differ from that underlying their effect on mood. They are generally well tolerated and rates of adverse events are far lower than those reported in studies of the use of these agents for depression. The limited efficacy of clonidine suggests that adrenergic mechanisms may be involved and data are awaited for more specific selective noradrenaline reuptake inhibitors. Thus, non-hormonal treatments are not as effective as estrogens in relieving hot flushes but may have a place as an alternative.

A review of non-hormonal options for the relief of menopausal symptoms.

The climacteric syndrome involves a variety of symptoms such as profuse sweating, insomnia, memory loss, decreased sexual drives, joint aches, and anxiety. However, amongst these symptoms, hot flashes and sweats are generally considered the hallmark and result in the majority of the medical consultations for this condition. Hot flashes are known to respond readily to placebo, which alone decreases their frequency by 20-40%. In the ideal setting of clinical trials, with optimal patient selection and compliance, estrogen therapy reduces hot flashes by about 70-80%; this is twice as effective as placebo. However, estrogen is unable to be universally used, either because of contraindications or because of an unwillingness of women to take it. Furthermore, hot flashes may persist in spite of adequate estrogen replacement, and physicians are often faced with the dilemma of finding something to administer in place of, or in addition to, estrogen to improve symptoms. The most commonly used non-hormonal alternatives for climacteric symptoms are neurotransmitter modulators such as serotonin reuptake inhibitors and gabapentin. These are, at best, approximately half as effective as estrogen for the relief of menopausal symptoms, and are only marginally better than placebo.Complementary treatment, particularly over-the-counter phytotherapeutic extracts, are very popular and women often try a variety of such products before resorting to conventional medicine. Preparations containing isoflavones, such as soy extract and red clover or extracts from evening primrose or cimicifuga (black cohosh, Actaea racemosa, syn. Cimicifuga racemosa), in variable doses are very popular for the treatment of hot flashes. The scientific support for their efficacy certainly does not equal their popularity.Non-hormonal treatments for menopause are not as effective as estrogens in relieving hot flashes, but may have a role in therapy for women who have contraindications to gonadal steroid use.

Critical review of health effects of soyabean phyto-oestrogens in post-menopausal women.

A consensus view of soyabean phyto-oestrogens in clinical interventions in post-menopausal women is presented that is based on data from the EU-funded project Phytohealth. The phyto-oestrogens, primarily genistein and daidzein, were given as soyabean-protein isolates, whole-soyabean foods or extracts, supplements or pure compounds. A comprehensive literature search was conducted with well-defined inclusion or exclusion criteria. For areas for which substantial research exists only placebo-controlled double-blind randomised controlled trials (RCT) conducted on healthy post-menopausal women were included. For emerging areas all available human studies in post-menopausal women were reviewed. In order to make cross comparisons between studies the doses of isoflavones were calculated as aglycone equivalents. There is a suggestion, but no conclusive evidence, that isoflavones from the sources studied so far have a beneficial effect on bone health. The consumption of whole-soyabean foods and soyabean-protein isolates has some beneficial effects on lipid markers of cardiovascular risk. The consumption of isolated isoflavones does not affect blood lipid levels or blood pressure, although it may improve endothelial function. For menopausal symptoms there is currently limited evidence that soyabean-protein isolates, soyabean foods or red-clover (Trifolium pratense L.) extract are effective but soyabean isoflavone extracts may be effective in reducing hot flushes. There are too few RCT studies to reach conclusions on the effects of isoflavones on breast cancer, colon cancer, diabetes or cognitive function. The health benefits of soyabean phyto-oestrogens in healthy post-menopausal women are subtle and even some well-designed studies do not show protective effects. Future studies should focus on high-risk post-menopausal women, especially in the areas of diabetes, CVD, breast cancer and bone health.

Vaginal polyps and hormones--is there a link? A case series.

Fibroepithelial stromal polyps (FSP) of the vault after hysterectomy are an uncommon, though well recognised finding. Both tibolone and tamoxifen have been reported to cause polyps in the endometrium but their connection with the same pathology in the vagina has never been described. Here, we report a case of a patient presenting with a symptomatic FSP 30 years after her hysterectomy while on treatment with both tamoxifen and tibolone. This prompted us to see if there was an association between these hormone-modulating agents with vaginal polyp formation. We reviewed all the cases notes of patients having FSP surgically removed in Hull over a 4 years period. Thirty-four women were identified. Some kind of hormonal influence, natural or otherwise, was found in 22 out of the 34 women. Endogenous or exogenous gonadal hormones or hormones modulators thus appear to influence the formation of vaginal polyps, but in this cohort a precise contribution of specific drugs could not be established.

Alternatives to estrogen to manage hot flushes.

Hot flushes are probably the most common symptom resulting in medical consultation in relation to the menopause and, when severe, they can affect quite dramatically women's quality of life. Hormone (estrogen) replacement therapy (HRT) is the most effective treatment for this symptom and in the ideal setting of clinical trials, under optimal selection of patients and compliance, it reduces hot flushes by about 70-80%. Recently, however, a series of 'scares' has had large resonance in the lay press about possible adverse effects of HRT. These have undermined both doctors' and women's confidence in the use of these compounds. This has been witnessed by the recent fall in HRT sales. A number of compounds, both pharmacological and herbal in origin, have been used for the treatment of neurovegetative symptoms in menopausal women. The present article critically reviews evidence of the efficacy of some of the most commonly used compounds and assesses their effect in relation to that of HRT.

Effects of raloxifene on mood, sleep, libido and cognitive function in postmenopausal healthy women: a pilot study.

OBJECTIVE: To assess the effect of raloxifene (60 mg) on psychological functions. MATERIAL AND METHODS: A total of 49 women were enrolled in a 3-month case-control study. Psychological testing was performed at baseline and at the end of 3 months of treatment. On both occasion measurements were repeated twice at 1 week apart. Scores were averaged. RESULTS: Raloxifene appeared to adversely affect the performance in the letter search test hence to worsen attention (t19 = 3.55, P = 0.002) but it reduced wakening episodes compared with baseline (t19 = 3.33, P = 0.005). Memory improved compared with baseline both in the raloxifene group (t19 = 2.99, P = 0.008) and in the controls (t19 = 4.64, P = 0.003). No significant differences were found in mood, well-being and indices of sexual activity. CONCLUSION: Raloxifene does not appear to adversely affect psychological function such libido, mood and memory. It may worsen attention but it reduces wakening episodes so it may thus improve sleep.

Gabapentin for the management of hot flushes: a case series.

OBJECTIVE: To audit the effectiveness of the anticonvulsant gabapentin on hot flushes in postmenopausal women. DESIGN: This was an open case series involving 11 postmenopausal women who were willing to take gabapentin for the relief of their hot flushes and were willing to keep a diary recording the number and intensity of their hot flushes, both before and during treatment. Gabapentin was started at a dose of 300 mg, to be taken at night, and the women were instructed to increase the dose up to 1,200 mg, according to symptom behavior. RESULTS: Eleven women agreed to participate for on average 53.22 days (range, 2-79 days), but two discontinued participation-one before starting treatment and one after 2 days-so there are complete data sets for nine women. Gabapentin was found to be extremely effective in reducing hot flush activity (P < 0.001; Fig. 1). A significant reduction in symptoms was observed with a dose of 300 mg/day (P < 0.001). Scores on the Green Climacteric Scale were significantly improved from a mean of 25.72 (range, 12-42) to 19.25 (range, 13-31; P < 0.001). Palpitations (P = 0.001), panic attacks (P = 0.0001), mood (P = 0.023), muscle and joint pains (P = 0.021), and paresthesias and loss of sensation in the extremities (P = 0.001) were also shown to improve with treatment. CONCLUSIONS: In the present case series, gabapentin was well tolerated and could be a valuable alternative for the treatment of hot flushes in women with contraindications to hormonal replacement therapy. It would be particularly beneficial for women in whom aches and pains and paresthesias are also a significant feature of the climacteric syndrome.

Hyperparathyroidism in elderly osteopenic women.

Raised levels of parathyroid hormones (PTH) predispose to osteoporotic fracture particularly in the elderly. The true prevalence of primary or secondary hyperparathyroidism is unknown, as PTH evaluation is not performed as a screening test in the elderly. We report raised PTH levels in 27 of 190 (14.2%) community living fully mobile postmenopausal women with densitometrically established osteopenia, consuming an average of 645 (+/-191) mg of calcium per day. Twenty-five of the 27 women with raised PTH were normocalcaemic, hypercalcaemia been found only in two. Serum 25 hydroxy vitamin D levels were all within the normal range (above 22 nmol/l). Women with a raised PTH were significantly older and their serum 25 hydroxy vitamin D levels were significantly lower than those women with normal PTH values. These data suggest that in community leaving healthy postmenopausal women, normocalcaemic hyperparathyroidism, in the presence of what are still considered normal vitamin D levels, may be common. This may suggests that widespread supplementation with calcium and vitamin D may be required in postmenopausal women for PTH suppression and preservation of bone mass.

The nature and utility of the phytoestrogens: a review of the evidence.

Non-prescription remedies are becoming increasingly popular particularly amongst postmenopausal who in this market are the largest consumers. Phytoestrogens are a large family of plant derived molecules possessing various degrees oestrogen like activity. Food or food supplements containing phytoestrogen are often been advocated as an alternative to hormonal replacement therapy (HRT) in women with contraindications to the use of conventional oestrogen replacement, or simply wanting a more 'natural' alternatives. There have been several studies performed with phytoestrogen in various aspects of the postmenopausal women health. Results have been sometimes conflicting and difficult to interpret. The lack of knowledge of what precisely is the active ingredient, its minimally effective doses, the lack of standardisation of the preparations used as well as the large individual variability of metabolism of precursors introduced with the diet may all have played a role in confusing the issue about effectiveness of these compounds. Phytoestrogen fall in the gray area between food and drugs hence in spite of the vast public interest, there are no interests in company producing these supplements in investing in research from which they will not exclusively benefit from. It is difficult for the physician to know how to advise patients on this matter. In this paper we critically review the clinical data available to date in an attempt to answer some of the most commonly asked questions about dose and type of phytoestrogens supplementation most likely to be effective in different aspects of climacteric woman health.

Polyunsaturated fatty acids. Is there a role in postmenopausal osteoporosis prevention?

OBJECTIVE: To review the effect of a diet supplemented with polyunsaturated fatty acids (PUFA) on prevention or treatment of osteoporosis. METHODS: MEDLINE (1966-April 2001), Allied Complementary Medicine (1985-2001), Cochrane Library and Database of Systematic Reviews (1st Quarter 2001) was searched. Five reviews and no systematic reviews were found on this topic in the Cochrane Library. Eleven relevant in-vivo studies were identified on the effect of these compounds on bone. Eight were animal studies and three were randomised control trials (RCT) in human. RESULTS: There are two classes of PUFA designated as n-3 and n-6 with alpha-linolenic acid (ALA). These two different types of PUFA differently influence prostaglandin formation and hence modulate bone metabolism differently. These are several in vitro and animal data suggesting that diet with a low n-6/n-3 ratio may have beneficial effects on bone mineral density. Only three, short-term, small studies have been performed in human so far. Two studies, one performed with bone markers and one with bone density showed a positive effect of PUFA on bone. While a third study showed no effect. CONCLUSIONS: Preliminary, data have suggested that a diet with a low n-6/n-3 ratio may have beneficial effects on bone mineral density. Further studies are, however, required to fully assess the dose and type of PUFA to be used for optimum bone effects. This may be useful particularly for the prevention of disease in the elderly, since a diet rich in n-3 PUFA has been shown to have additional benefit on the cardiovascular, central nervous system and joints.

Management of hot flushes without oestrogen.

Hot flushes are probably the most common symptom resulting in medical consultation in relation to the menopause. The association between the two is so strong that the connection is often invoked even when hot flushes occur in a regularly menstruating woman. Oestrogen significantly reduces hot flushes but is not used by all women-either because of contraindications or a reluctance to take oestrogen-based therapy. In addition, hot flushes may persist in spite of adequate oestrogen replacement, and physicians are often faced with the dilemma of finding something instead of, or in addition to, oestrogen for symptom relief. The available alternatives for the management of hot flushes are reviewed.