Vulva and Vagina

The lower genital tract undergoes atrophic changes with loss of connective tissue elasticity and thinning of the mucosa. There is a decline in intracellular glycogen production in the vagina, leading to a decrease in lactobacillae and lactic acid and an increase in the vaginal pH from acid to alkaline. These changes lead to an increase in colonization by pathogenic bacteria and infective vaginitis. Senile or atrophic vaginitis is also common due to loss of vaginal tissue elasticity and shrinkage of the vagina with subsequent loss of lubrication. This can lead to postmenopausal bleeding and dyspareunia.

Cervix and Uterus

The cervix becomes atrophic and the ectocervix becomes flush with the vaginal vault. The squamocolumnar junction of the cervix recedes into the endocervical canal and it becomes difficult to obtain an accurate representative cervical smear. The uterus undergoes atrophy of myometrium and the uterine body becomes smaller. The endometrium becomes thinner and the glands become inactive.

Ovary and Fallopian Tube

In the perimenopausal years, the few remaining primordial follicles become unresponsive to the pituitary gonadotrophins and therefore the estrogen secretion falls. The ovaries become smaller and more wrinkled in appearance. The fallopian tubes become shorter with muscle replaced by fibrous tissue.

Pelvic Floor

Pelvic floor muscle weakness is due to the combined effects of estrogen withdrawal and age. This is compounded by the mechanical effects of previous childbirth. The endopelvic fascia surrounding both the genital tract and urinary tract atrophies. The fascial condensations of cardinal and uterosacral ligaments also atrophy, leading to an increased incidence of genital prolapse as age increases. In the elderly, chronic cough, constipation and increased intra-abdominal pressure are other factors contributing to this.

Urethra and Bladder

Both the urethra and trigone of the bladder are sensitive to estrogen as they have estrogen receptors and there is deterioration in structure and function as a woman ages. The urethral lumen becomes more slit shaped and the folds become coarser. The mucosal lining changes from transitional in the proximal two-thirds to non-keratinizing squamous epithelium.2 Urethral closure becomes less competent. There is a reduction in detrusor contraction power during voiding and the contractions fade shortly after initiation of voiding. Bladder capacity is also reduced in the elderly. All these features contribute to the greater prevalence of urinary incontinence in elderly women. Estrogen withdrawal may also lead to a high prevalence of urinary tract infection in the elderly, which is aggravated by voiding difficulty and may lead to stress incontinence, urge incontinence, frequency, urgency and nocturia.3

In premenopausal women, ovarian function is controlled by the two pituitary gonadotrophins, follicle stimulating hormone (FSH) and luteinizing hormone (LH). These are controlled by the pulsastile secretion of gonadotrophin releasing hormone (GnRH) from the hypothalamus. The ovary has the maximum number of oocytes at 20–28weeks of intrauterine life. There is a reduction in these cells from mid-gestation onwards and the oocyte stock becomes exhausted in the perimenopausal age group. The ovary gradually becomes less responsive to gonadotrophins resulting in a gradual increase in FSH and LH levels, and a fall in estradiol concentration. As ovarian unresponsiveness becomes more marked, cycles tend to become anovulatory and complete failure of follicular development occurs. Estradiol production from the granulosa and theca cells of the ovary ceases and there is insufficient estradiol to stimulate the endometrium; amenorrhoea ensues. FSH and LH levels are persistently elevated. FSH level >30 IU l−1 is generally considered to be the postmenopausal range

Menopause is defined as the permanent cessation of menstruation. The word menopause is derived from the Greek words menos (the month) and pausos (ending). It is a retrospective diagnosis since a woman is menopausal only after 12 months of amenorrhoea. The average age of menopause is 51 years and the female life expectancy is now over 80 years. Postmenopausal women spend more than 30 years in a profound estrogen-deficient state. The early symptoms of menopause are vasomotor symptoms, principally hot flushes, night sweats and insomnia. The long-term consequences are osteoporosis, urogenital atrophy, cardiovascular disease and connective tissue atrophy.

Vasomotor Symptoms

There is good evidence from randomized placebo-controlled studies that estrogen is effective in treating hot flushes and improvement is noted within four weeks.4 Relief of vasomotor symptoms is the commonest indication for HRT and current recommendations for the duration of use is for up to five years. In general, as old age approaches, the symptoms of the menopause appear to resolve spontaneously, though of course, the risk of osteoporosis increases. However, there are a small proportion of women whose menopausal symptoms (hot flushes in particular) last well into later life. Since non-hormonal treatments for hot flushes are universally ineffective management of this group can be a challenging problem. There is subsequently a small group of women who request HRT well beyond the five years normally recommended.

Osteoporosis

Osteoporosis has been defined by the World Health Organization (WHO) as a ‘disease characterized by low bone mass and micro-architectural deterioration of bone tissues, leading to enhanced bone fragility and a consequent increase in fracture risk’. In postmenopausal women, there is accelerated bone loss, so that by the age of 70 years, 50% of bone mass is lost. The risk factors for osteoporosis include family history, low BMI, cigarette smoking, alcohol abuse, early menopause, sedentary lifestyle, corticosteroids. Fractures are the clinical consequences of osteoporosis. The most common sites of osteoporotic fractures are the distal forearm (wrist or Colles fracture), proximal femur and vertebrae. Vertebral fractures lead to loss of height and curvature of the spine with typical dorsal kyphosis (‘Dowager’s hump’). This affects their overall QOL and may ultimately impair respiratory function. There is evidence from randomized controlled trials that HRT reduces the risk of osteoporotic fractures.5, 6 However, recent advice from regulatory authorities has been that HRT should not be used for osteoporosis prevention as the risks of such treatment outweigh the benefits.7 After the publication of the Million Women study in 2003, the Committee on Safety of Medicines (CSM) pronounced that HRT was no longer to be considered as first-line therapy for the prevention of osteoporosis. Bisphosphonates may be the best choice for the over 60s, though there is actually less data on long-term safety.

Urogenital Symptoms

Symptoms such as vaginal dryness, soreness, superficial dyspareunia and urinary frequency and urgency respond well to local estrogen, in the form of pessaries, rings and tablets. Estradiol tablets (Vagifem® Novo Nordisk) are associated with minimal or no systemic absorption. In light of this it is believed that long-term use of Vagifem is safe in contrast with other vaginal estradiol preparations. However, there is currently no clear evidence to support its long-term safety,

Risks of HRT

Breast Cancer

HRT appears to confer a similar degree of risk as that associated with late natural menopause. In absolute terms, the excess risk in the Women’s Health Initiative (WHI) study with continuous combined HRT at 50–59 years was 5; 60–69 years, 8; and 70–79 years, 13 cases of breast cancer per 10 000 women per year.8 The unopposed estrogen-only arm of this study did not show any evidence of an excess increase in breast cancer risk. The Million Women study found an increased risk with all HRT regimens, the greatest degree of risk was with combined HRT.9 So the addition of progestogen increases breast cancer risk compared with estrogen alone but this has to be balanced against the reduction in risk of endometrial cancer provided by combined therapy.8, 10 Irrespective of the type of HRT prescribed, breast cancer risk falls after cessation of use, risk being no greater than that in women who have never been exposed to HRT by five years.

Endometrial Cancer

Unopposed estrogen replacement therapy increases endometrial cancer risk. Most studies have shown that this excess risk is not completely eliminated with monthly sequential progestogen addition especially when continued for more than five years. No increase has been found with continuous combined regimens.11 Administration of the progestogen by the intrauterine route (Mirena® (levanorgestrol-releasing system) ) would seem to have the benefit of maximal endometrial dose with low systemic effects.

Venous Thromboembolism

HRT increases risk of venous thromboembolism (VTE) twofold with the highest risk occurring in the first year of use. Advancing age and obesity significantly increase this risk. The absolute rate increase is 1.5 VTE events per 10 000 women in one year. This risk is lower with transdermal estradiol compared to oral due to avoiding the first pass metabolism effect in the hepatic circulation.

Cardiovascular Disease (Coronary Heart Disease and Stroke)

The role of HRT either in primary or secondary prevention of cardiovascular disease remains uncertain and so it should not be used primarily for this indication. The WHI study showed an early transient increase in coronary events. The excess absolute risk at 50–59 years was 4; 60–69 years, 9; and 70–79 years, 13 cases of stroke per 10 000 women per year. However, the timing, dose, and possibly type of HRT may be crucial in determining cardiovascular effects. In hypertensive patients it is recommended that once the blood pressure is under control estrogen can be given. Therefore, HRT should currently not be prescribed solely for possible prevention of cardiovascular disease. The merits of long-term use of HRT need to be assessed for each woman at regular intervals. It should be targeted to the individual woman’s needs.

Alzheimer’s Disease

While estrogen may delay or reduce the risk of Alzheimer’s disease, it does not seem to improve established disease. WHI study found a twofold increased risk of dementia in women receiving the particular combined estrogen and progestogen regimen. However, this risk was only significant in the group of women over 75 years of age. More evidence is required before definitive advice can be given in relation to Alzheimer’s disease.