Urogenital atrophy.

The British Menopause Society Council aims to aid health professionals in providing up to date and informed advice about post reproductive health. This guidance refers to the long-term, but often ignored condition of urogenital atrophy resulting from postmenopausal estrogen deficiency. Treatment should be based on up to date information and targeted to the needs of the individual woman. Non-estrogen- and estrogen-containing treatments are discussed.

Cancer issues.

The potential for hormone therapy to cause cancer is the greatest fear for postmenopausal women considering hormone replacement therapy (HRT). Breast cancer is the most common female malignancy, for which HRT is one of many modifiable risk factors, often attracting disproportionate attention. Randomized controlled trials have confirmed that in postmenopausal women aged 50-59 years taking combined oestrogen and progestogen HRT over 5 years, there will be three extra cases of breast cancer per 1000 women. With the use of unopposed conjugated equine oestrogens, there would be four fewer cases over the same time. Women can be advised that the risk of breast cancer is not significantly increased with up to 3 years of combined HRT and up to 5 years of unopposed oestrogen. Unopposed oestrogen increases the risk of endometrial hyperplasia and carcinoma significantly, and this is dose and duration dependent. The addition of progestogen prevents the proliferative effect of oestrogen on the endometrium, and may even reduce the risk of endometrial cancer compared with non-users if given continuously. The use of combined oral contraception in premenopausal women also reduces the risk of endometrial cancer but increases the risk of cervical carcinoma significantly. HRT does not influence the risk of cervical cancer. Epithelial ovarian cancer risk may be slightly increased with long-term use of unopposed oestrogen, is not altered by the addition of progestogen, and is reduced significantly in users of combined oral contraception. The mechanism for these effects is not understood. Colorectal cancer and possibly lung and gastric cancers are reduced by the use of HRT. Apart from a slight increased risk of gallbladder disease and carcinoma with HRT, there are no data linking oestrogen or progestogen with any other malignancies.

The menopausal hot flush--anything new?

Although the hot flush is generally recognised by women and the medical profession as the most characteristic and often a very distressing symptom of the climacteric, it remains an enigma. The physiological changes associated with the hot flush are different from any other flushing condition, with an increased peripheral blood flow, increased heart rate and in particular a decrease in galvanic skin resistance, which is unique to the flush. Flushing occurs as a result of disturbance of the temperature regulating mechanism situated in the hypothalamus, and probably a reduction in the thermoneutral zone, within which fluctuations of basal body temperature do not provoke compensatory vascular responses. Many factors have been implicated, including hormone releasing factors, gonadotrophins and neurohumorals. However, the role of oestrogen is critical and the clinical value of oestrogen therapy is well established and has been confirmed by a Cochrane review. Nevertheless, the precise mechanism by which reduced circulating levels of oestrogen are involved in causing the flush has not yet been established. Priming with oestrogen seems to be an essential pre-requisite for flushing, as young women with ovarian dysgenesis and very low circulating levels of oestrogen never have hot flushes unless they are given oestrogen replacement therapy, which is later discontinued. Oestrogen antagonist activity by selective oestrogen receptor modulators such as tamoxifen and raloxifene can also cause flushing. A link with gonadotrophins is demonstrated by a temporal association of flushes with the pulsatile release of luteinising hormone (LH). However, if LH pulses are eliminated by GnRH analogue, the frequency of flushing is not altered, which confirms that LH is merely associated with the flush rather than being causative. It is probable that the flush is initiated by a supra-pituitary mechanism which is influenced by the hypothalamic factors responsible for pulsatile LH release. A variety of chemical pathways have been proposed involving serotonin, noradrenalin and dopamine. Trials of drugs that selectively inhibit the re-uptake of serotonin and noradrenalin have shown some beneficial effects, as also has gabapentin, but often the results have been disappointing, and certainly less than the response seen with oestrogen or tibolone. The prevalence of hot flushes varies considerably around the world and is less in the Far East than in the west. Differences in diet and in particular the intake of phytoestrogens has been implicated and many studies have tried to establish whether dietary supplementation with phytoestrogens might be a suitable alternative to conventional hormone replacement therapy (HRT). So far, the results are disappointing. Other lifestyle measures such as avoiding alcohol, caffeine and spicy foods, keeping the core body temperature cool, paced respiration, taking exercise and even acupuncture may help. Hot flushes remain a major cause of reduced quality of life in a large proportion of menopausal women, but perhaps because they are not fatal and are usually self-limiting, there has been rather limited research or clinical interest. However, for the increasing number of women being treated with tamoxifen for breast cancer, and for whom oestrogen will usually be contra-indicated or unsuitable, there is an urgent need to identify the underlying mechanism so that appropriate, specific and safe non-oestrogen therapy can be offered to improve their quality of life.

Expression of calcitonin gene-related peptide, adrenomedullin, and receptor modifying proteins in human adipose tissue and alteration in their expression with menopause status.

OBJECTIVE: Calcitonin gene-related peptide (CGRP) is a vasoactive, proinflammatory neuropeptide implicated in the pathogenesis of cardiovascular disease. Elevated CGRP levels during hot flushes and pregnancy suggest that reproductive hormones may influence CGRP secretion. CGRP and the related protein adrenomedullin (ADM) may function through adipose tissue-mediated effects, since adipose tissue is an important site of cytokine production and the main site for estrogen production after menopause. This study examined mRNA and protein expression of CGRP, ADM, and the receptor activity-modifying proteins and the effects of menopausal status in human adipose tissue. DESIGN: Protein/mRNA levels were determined in adipose tissue biopsy samples collected from premenopausal (n = 22: follicle-stimulating hormone, <20 IU/L; estradiol [mean +/- SEM], 434.5 +/- 87.81 pmol/L) and postmenopausal (n = 25: follicle-stimulating hormone, >20 IU/L; estradiol, 43.4 +/- 6.95 pmol/L) women. RESULTS: Our studies determined that CGRP, ADM, and receptor activity-modifying proteins were expressed in abdominal fat, adipocytes, and preadipocytes. CGRP and ADM mRNA levels were increased in abdominal subcutaneous fat in postmenopausal women compared with premenopausal women (betaCGRP: premenopause Delta cycle threshold [Ct], 31.07 +/- 0.28 vs postmenopause DeltaCt, 30.35 +/- 0.17, P = 0.035; ADM: premenopause subcutaneous fat DeltaCt, 12.41 +/- 0.2 vs postmenopause subcutaneous fat DeltaCt, 11.55 +/- 0.14, P < 0.001) with CGRP differentially expressed in subcutaneous and omental depots. CGRP protein expression was higher in postmenopausal women (P < 0.05) in both fat depots. CONCLUSIONS: Our findings suggest that adipose tissue represents an important site for CGRP and ADM production and that menopause status alters their expression in abdominal fat. This offers a potential mechanism to explain the role of CGRP in menopausal vasomotor symptoms and the increased risk of cardiovascular disease in postmenopausal women.