Hormone Replacement Therapy and Menopause

Menopause refers to the final menstrual period a woman experiences and marks the end of a woman’s reproductive life. The ovaries no longer release eggs and also stop producing the hormones oestrogen and progesterone. Natural menopause is usually experienced by women between 45 and 55 years of age. In Australia, the average age of onset is 51 years.

Physical symptoms experienced by women are mainly due to declining hormone levels, particularly oestrogen. Around 60% of women will have mild symptoms for around five to eight years, 20% will have no symptoms, and 20% will have severe symptoms.

Vasomotor symptoms are experienced by up to 80% of women during menopause and include hot flushes, night sweats, and formication (a sensation that feels like ants crawling on the skin). Vaginal symptoms include vaginal dryness, loss of libido, dyspareunia, and atrophic vaginitis. Urinary symptoms include urge incontinence and recurrent urinary tract infections. Weight gain, osteoporosis, body aches, unwanted hair growth, thinning of scalp and pubic hair, skin changes, and increased bleeding gums are other possible symptoms.

These physical symptoms can have an impact on a woman’s quality of life. Hormone replacement therapy (HRT) may be considered for symptom relief. Oestrogen is prescribed to relieve the symptoms caused by the reduced endogenous production of oestradiol. Women with a uterus also require a progestogen for at least ten days a month to prevent endometrial cancer associated with unopposed oestrogen.

The lowest effective dose of oestrogen should be prescribed, and appropriateness of therapy reviewed every six to twelve months. Oral formulations are often preferred as they are safe and effective and also less expensive than other dosage forms. Transdermal therapy may be considered for women who smoke, have trialled high oral doses that are ineffective, take medications that inhibit absorption or hepatic metabolism of oral formulations, have a history of major bowel or liver issues, Crohn’s disease or ulcerative colitis, uncontrolled hypertension, malabsorption, or irritable bowel syndrome. Vaginal oestrogen is preferred in women whose symptoms are primarily urogenital. Systemic absorption is minimal when these formulations are used at the recommended doses. Therefore, progesterone cover is not usually necessary for women with a uterus. Vaginal oestrogen may also be used when women on systemic HRT continue to experience vaginal symptoms. Vaginal tablets are better tolerated than pessaries and creams as they cause less vaginal discharge.

A review of HRT therapy should be made after a three-month trial. Tolerance to adverse effects may develop during the first few months of use. For adverse effects that persist and are troubling, the following management strategies are recommended.

• Oestrogen-related adverse effects such as breast enlargement or tenderness, fluid retention, headache, leg cramps, and nausea may respond to a reduction in dose, change of oestrogen, or a different route of administration.
• Nausea may be minimised by taking tablets with food or at night.
• Progesterone-related adverse effects such as breast tenderness, fluid retention, headache, depression, premenstrual-like syndrome, and acne may be minimised by changing the progesterone, reducing the dose, changing the route, reducing the duration of progesterone to ten days per month, or changing to a three-monthly cyclical regimen or continuous combined HRT.

Results from the Women’s Health Initiative (WHI), the largest randomised controlled trial ever conducted in this field, caused many women to abandon HRT use. However, it has been argued that many of the risks presented in this study were not appropriately put into clinical perspective. Re-analysis of trial findings on HRT and breast cancer shows that the increased risk is primarily associated with the addition of a progestogen to oestrogen therapy. In addition, no significant increased risk was observed with combined therapy in the first seven years of use in women who had not previously taken HRT. Although this increased risk was highly publicised, it equates to eight additional cases per 10,000 women-years. For women between 50-59 years of age, the International Menopause Society states that HRT remains the first-line treatment for vasomotor symptoms and urogenital atrophy associated with menopause.  HRT has consistently demonstrated a superior efficacy in reducing hot flushes compared to other therapies. Oestrogen alone or in combination with progesterone has been shown to reduce weekly symptom frequency by 75% as well as reducing symptom severity.

Results of the WHI demonstrated an increased risk of stroke with HRT. However, this risk is low in women younger than 60 years of age with normal blood pressure. The risk of venous thromboembolism (VTE) is also elevated, especially with increasing age and risk factors like previous thromboembolism, smoking, and immobility. Again, the risk is lower in women younger than 60 years. The risk of VTE and stroke may be lower with transdermal oestrogen compared to standard doses of oral oestrogen. More recent findings suggest that coronary heart disease and all-cause mortality may be reduced when HRT is initiated close to the onset of menopause. However, these benefits seem to be lost when HRT is initiated more than ten years after the onset of menopause. Data from observational studies suggest that the risk of cardiovascular disease may increase in these cases. Overall, women may be assured that the absolute risk of complications is low in healthy, young postmenopausal women taking HRT for five years.

The 2017 Position Statement from the North American Menopause Society (NAMS) encourages prescribers to tailor HRT to the individual to maximise benefits and minimise the risks. Use of HRT regimens at an appropriate dose, duration, and route of administration will provide patients with the most benefit while minimising the risks associated with therapy. Risk stratification of patients based on their age and time since menopause may provide further benefits. The current evidence-based recommendations from NAMS state that, for symptomatic women younger than 60 years or who are within ten years of menopause onset, the potential rare increased risk of breast cancer should be weighed against the significant positive effects of HRT on coronary heart disease and all-cause mortality.

HRT is contraindicated in women who have had breast cancer or another type of oestrogen-dependent tumour. Non-hormonal treatments are recommended in such cases. HRT is also contraindicated in women who have cerebrovascular or coronary artery disease, severe liver disease, history of a thromboembolic disorder, or uncontrolled hypertension. HRT should be avoided in women who are not in remission for systemic lupus erythematosus as it may exacerbate the condition. Caution should be exercised in women with unexplained vaginal bleeding, endometriosis, uterine fibroids, migraines, epilepsy, hypertension, gall bladder disease, and women over 60 years of age. Enzyme-inducing medicines may increase oestrogen clearance, resulting in reduced efficacy. The oestrogen dose can be re-titrated when initiating or ceasing an enzyme-inducing medication. HRT should ideally be withheld for four to six weeks before elective surgery due to the increased risk of postoperative VTE.

A variety of hormone replacement therapy (HRT) preparations is available as shown in Table 1.

Table 1. Hormone replacement therapy products

*Selective oestrogen receptor modulator.

For women with an intact uterus, the progestogen component of their therapy may be provided in a fixed-dose or combination formulation. Other options for the provision of adjunctive progestogen include norethisterone (Primolut N^®), progesterone (Prometrium^®) or medroxyprogesterone (Provera^®) tablets or a levonorgestrel intrauterine device (Mirena^®).

Women considering HRT should discuss the benefits and risks of HRT relative to their stage in life with their physician. It is also recommended that they have a pretreatment breast check and mammogram as oestrogen can promote the growth of an existing subclinical breast cancer. The decision to use HRT must be reviewed annually by the woman in consultation with her doctor.