Vasomotor symptoms and mood

The activity of the hypothalamus in the regulation of temperature, satiety/ appetite and blood pressure, and of the limbic system in regulation of mood and psychologic well-being, seems to be influenced by estrogen. Estrogen deficiency at these specific sites in the central nervous system (CNS) is thought to be responsible for the vasomotor symptoms of hot flashes, night sweats, palpitations and mood swings experienced by over 60% of climacteric women. The hot flash of heat is a subjective sensation associated with cutaneous vasodilation and a subsequent drop in core body temperature. The hot flash may be accompanied by visible redness in the neck and face area, sweating or even panic. It is typically described as starting from somewhere around the mid-torso and moving upwards to the face. This intensely unpleasant sensation can last from seconds to minutes, usually within the range of 3-4 min. The precise mechanism underlying hot flashes is unclear, but altered thermoregulatory control from the hypothalamus is believed to be partially responsible. These manifestations of vasomotor instability show a diverse range of intensity between women, and at worse can be extremely disruptive to a woman’s quality of life. The symptoms associated with the surgical menopause are more abrupt and severe and can last longer than those associated with the natural menopause. Smoking, lack of exercise and being underweight are associated with an increased risk of hot flashes. Hot flashes and their differential diagnosis are discussed in more detail in site. Estrogen therapy is an effective treatment in reducing both the frequency and intensity of these vasomotor symptoms, and higher estrogen doses may be required in hysterectomized women. Medroxy-progesterone acetate (MPA) and norethisterone acetate (NETA) are moderately effective in treating hot flashes in women who do not want to take estrogen or in whom estrogens are contraindicated. Tibolone (synthetic compound with estrogenic, progestogenic and androgenic activity) is also effective against hot flashes and is used as an alternative to hormone replacement therapy. Recent randomized controlled trials produced data showing that long-term hormone replacement therapy may not be as safe as originally thought. This may lead to renewed interest in clonidine. The latter is moderately more affective than placebo in relieving hot flashes but it can cause sedation or dry mouth in some patients. It is licensed for treatment of hot flashes and the usual dose is two tablets of 25 mg twice a day. Phytoestrogens have been studies as a natural remedy for hot flashes as well. The results from controlled trials suggest that the effect is moderate at best and tends to be more pronounced in women with more severe hot flashes. New treatments for hot flashes are now being tested. In small controlled clinical trials, gabapentin, venlafaxine and fluoxetine were found to be more effective than placebo. However, their use in daily clinical practice is not yet established. Up to 40% of the female population experience adverse affective symptoms during the climacteric, ranging from mild anxiety states to depressive disorders, and a reduced sense of well-being. Although no definite hormonal link has been demonstrated, a beneficial effect of estrogen on quality of life measures has been demonstrated.

Urogenital system

Lower genital tract

Estrogen receptors (ERs) occur in the tissues of the vagina, urethra, bladder and pelvic floor, consistent with the fact that the lower parts of the female genital and urologic tracts share a common embryologic origin from the primitive urogenital sinus. Prolonged estrogen deficiency leads to vaginal atrophy and the classic symptoms of vaginal dryness, itching, burning and dyspareunia. Apart from the unpleasant feeling of dryness, vaginal atrophy predisposes to vaginal infection and sexual dysfunction. Estrogen replacement, whether local or systemic, has been shown to be effective in treating atrophic vaginitis, vaginal dryness and infection. Estrogen replacement leads to improved lubrication and enhancement of the pleasurable sensations experienced during sexual stimulation.

Lower urinary tract

Estrogen deficiency has been linked to urologic complaints such as frequency, nocturia, incontinence, urinary tract infections and the ‘urge syndrome’. The increase in prevalence of urinary incontinence with age may be related to the menopause and diminishing estrogen levels. ERs have been demonstrated in the urinary tract. Stress incontinence arises when the urethral closure pressure is exceeded by the intravesical pressure. Estrogen may exert beneficial effects on the positive urethral closure pressure by a combination of increased urethral cell maturation and periurethral collagen production, increased blood flow and increased a-adrenoreceptor sensitivity in the urethral smooth muscle. However, recent studies have shown that the menopause has not been specifically linked to the onset of stress incontinence and may be only one of several contributing factors. Contrary to popular belief, estrogen replacement does not appear to help with stress incontinence. Estrogens may help in the urge syndrome and urge incontinence by raising the sensory threshold of the urethra and bladder. It is not clear if estrogens reduce the incidence of lower urinary tract infection.

Skin, connective tissue and cartilage

The menopause may affect all organs containing connective tissue. Estrogen and androgen receptors have been found on dermal fibroblasts, and further work has demonstrated the presence of receptors in the epidermis, hair follicles, sebaceous glands and eccrine glands and vessels. Postmenopausal atrophy of the dermis results from a decrease in the dermal skin collagen content, which declines in the first five years after the menopause by up to 30%. It has been demonstrated that skin collagen content and skin thickness are increased in women on hormone replacement therapy compared to age-matched women on no treatment.

Middle-aged women commonly complain of polyarticular symptoms and this has fueled speculation that there may be a connection between arthritis and the menopause. The term ‘menopausal arthritis’ has been used to describe such complaints. ERs have been found on articular chondrocytes, but their significance is not clear. Population surveys and hospital-based studies have found that the prevalence of generalized osteoarthritis is three to ten times higher in middle-aged women than in men. Rheumatoid arthritis also shows a striking age and sex disparity. It appears earlier in women than in men and the female/male ratio is 2.3-3.7:1. hormone replacement therapy seems to improve arthritic symptoms, and may be a useful intervention in maintaining bone health in patients with rheumatoid arthritis who have an increased risk of osteoporosis. Although it may seem logical that hormone replacement therapy should be beneficial in maintaining joint health because of the abundance of ERs in connective tissue, there is no agreement on the role of hormone replacement therapy, if any, in these two types of arthritis.

Cardiovascular system


The central nervous system, cognition, Alzheimer’s disease and stroke

Colorectal cancer

Colorectal cancer has an incidence of 38 per 100 000 in England and Wales and is the second most common cancer in women in the UK. It is the third leading cause of cancer death and constitutes 15% of all cancers. Although colorectal cancer can occasionally occur at a younger age, most patients are in their sixth or seventh decade at diagnosis.

The cause of colorectal cancer is unknown but diet, genetic factors, adenomatous polyps and secondary bile acids have been implicated. The Nurses’ Health Study and other cohort studies suggested that postmenopausal hormone replacement use appeared to decrease the risk of cancer by about 35%, with ‘current’ use affording more protection than ‘past’ use. The protective effect disappeared five years after discontinuation of hormone use. Possible mechanisms explaining this effect on bowel cancer include the ability of estrogen to decrease the secondary bile acid production and its ability to suppress the growth of colonic epithelial cells. These results have been since confirmed in a randomized controlled trial, the WHI study. In this trial the incidence of bowel cancer was 10 per 10 000 woman-years on treatment and 16 per 10 000 woman-years on placebo, or absolute risk reduction was 6 per 10 000 woman-years and relative risk reduction was 37%.

Gums, teeth, wound healing and postural balance

The effects of the menopause and hormone replacement therapy on oral health, wound healing and balance are less well studied. The data so far show that ERT prevents tooth loss and gum disease, enhances wound healing and improves postural balance in postmenopausal women.

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