Compliance

Prescribing hormone replacement therapy is complicated by the difficulties in persuading an apparently healthy population of women to take a treatment for a considerable period of time with the aim of preventing potential illnesses later in life. Compliance with hormone replacement therapy, although often good in the short term, is usually poor in the longer term. This is due to a combination of factors including adverse side-effects, fears over breast cancer and poor understanding of long-term hormone replacement therapy benefits from sustained use. Almost 40% of women advised to start hormone replacement therapy for bone density preservation had discontinued treatment within eight months of starting in one study, mainly because of adverse side-effects (see Table Common side-effects of hormone replacement therapy).

Table Common side-effects of hormone replacement therapy

Estrogenic Progestogenic
Breast tenderness/enlargement Breast tenderness
Edema/bloating Bloating
Headache Headache
Nausea Acne/seborrhea
Leg cramps PMS symptoms
Vaginal discharge Depression
Eye irritation Dysmenorrhea
Breakthrough bleeding Libido changes
Insomnia
Lethargy
Scalp hair loss
Hirsutism

PMS, premenstrual syndrome

Choice of therapies

Changing the dosage or route of treatment can attenuate certain of the adverse effects of hormone replacement therapy. Beneficial metabolic effects of hormone replacement therapy have been demonstrated for the oral and transdermal routes of administration, and both routes have been shown to be effective in relieving postmenopausal symptoms, as well as beneficial in preventing postmenopausal bone loss. It is important to emphasize this to women about to embark on long-term treatment, since better compliance will usually follow if the patient is allowed free choice of her therapy or is encouraged to try alternatives if the first dosage or route of treatment is unacceptable. hormone replacement therapy can be given via various routes (Table Routes of administration of hormone replacement therapy), which should allow individualization of therapy.

Table Routes of administration of hormone replacement therapy

Route Preparation
Oral Tablets
Transdermal Patches
Gels
Vaginal Creams/gels
Rings
Pessaries
Subcutaneous Implants
Intramuscular Injection
Intranasal Spray

The basic hormonal substances used in hormone replacement therapy preparations are only few, but various routes of administration and dose permutations have led to more than 50 systemic and topical preparations currently being licenced for use in the UK. Commonly used estrogens are estradiol, CEE, estrone and estriol. Commonly used progestogens are dydrogesterone, levonorgestrel, medroxyprogesterone and norethisterone.

Traditionally, oral routes of administration have been most widely used for hormone replacement therapy. Long-term compliance with oral regimens has been poor, but with the advent of better and less irritant patches, both the oral and the transdermal routes are becoming increasingly popular and might be expected to encourage compliance, especially with the introduction of seven-day patches. In a recent study approximately 90% of women did not miss a single application of a matrix-type seven-day patch (FemSeven) over a period of 18 months. In addition, the newer matrix patches seem to represent an improved option over reservoir patches in terms of skin reactions and improved adhesion.

Knowledge of the pharmacokinetics of oral and transdermal estrogen is useful in predicting the possible effects of treatment via these two routes. Oral estrogens are subject to extensive first-pass metabolism before metabolically active compounds can act systemically. Thus, larger doses are required than with transdermal delivery systems, which avoid this firstpass effect. Oral estrogen administration is associated with alterations in bile composition which leads to a greater degree of gastrointestinal disturbance and increased risk of gallstone disease. The transdermal route is preferred in cases of chronic liver disease, liver transplant or history of gallstones. Oral estrogens are known to exert a beneficial effect on serum lipoprotein levels via their extensive hepatic metabolism, but recent studies have also shown that transdermal estrogens exert beneficial effect, albeit to a lesser extent, on cholesterol but to a greater extent on triglyceride values. Transdermal delivery systems tend to lead to a more stable serum estradiol level than with orally administered estrogen, and may be more appropriate, for example, in women using enzyme-inducing drugs or who smoke. Cigarette smoking is thought to reduce estradiol bioavailability via its effect on hepatic metabolism, but since transdermal estradiol avoids first-pass liver metabolism, it may be less affected than oral estrogen by the effects of cigarette use. There may be a theoretically lower risk of VTE with transdermally administered estrogen replacement. Although firm evidence is lacking, it is possible that patients suffering from conditions such as hypertriglyceridemia, fibrocystic breast disease or migraine may be better suited to transdermal therapy. In addition, transdermal therapy is a good alternative for women who prefer not to take daily oral medication or who absorb medications poorly because of gastrointestinal malabsorption syndromes (e.g., post-surgery, Crohn’s disease, etc.). Often, women ask for a blood estrogen level estimation. Generally, if the symptoms are controlled, the blood level is likely to be adequate and no estrogen blood level is necessary. Estradiol blood level measurement is sometimes indicated in anxious patients, if there are difficulties in symptom control or when monitoring estrogen treatment for osteoporosis. An estradiol level in excess of 200 pmol/1 is considered satisfactory. Typical plasma estradiol levels reported in pharmacokinetic studies are given in Table Mean estradiol blood levels with various hormone replacement therapy preparations.

Table Mean estradiol blood levels with various hormone replacement therapy preparations

Preparation Dose Level (pmoV1)
CEE 1.25 mg 110-125
Oral estradiol 1.0 mg 110-130
2.0 mg 200-225
Estradiol patches 50 ug/24 h 125-150
100ug/24h 250-350
Estrodiol gel (Oestrogel) 1.5 mg 225-250
3.0 mg 350^100
Estradiol gel (Sandrena) 1.0 mg 300^100
Vaginal ring (Menoring) 50 ug/24 h 150

CEE, conjugared equine estrogens

Oral estrogens, including CEE, give wise to plasma estrone levels. Estrone is 3-10 times less potent than estradiol and is not measured by most laboratories. In pharmacokinetic studies, usually only estradiol is studied and there are limited data on estrone. Estrone measurement is unnecessary when prescribing estradiol.

Patient profiling

Patients’ understanding of the menopause and the benefits of hormone replacement therapy use on their future health could be improved with dedicated well women clinics, leaflets and posters in the surgery. The initial assessment should include age of menopause and type (i.e., natural or surgical), presence of menopausal symptoms and their severity, risk factors for future heart disease, osteoporosis or other diseases potentially modified by hormone replacement therapy, and contraindications to hormone replacement therapy. Selection of the most appropriate dose and route of administration can then be made using the initial assessment according to the woman’s individual needs or co-morbid illness. This should improve patients’ satisfaction with care, allowing early intervention and tailoring of therapy, and should improve the take-up and continued use of hormone replacement therapy. Review of patients should occur at least every six months to ensure compliance, and more frequent follow-up visits may be necessary if unacceptable side-effects occur. Treatment can be altered as necessary if there are significant side-effects, or lack of symptom control. Early and easy access to a specialized menopause clinic should be offered to any patient with resistant symptoms or side-effects, or preexistent medical problems that may complicate postmenopausal hormone therapy. Breast and pelvic examinations should be performed if clinically indicated and routine mammography (every three years) should continue while hormone replacement therapy is being used.

Women about to undergo hysterectomy with or without oophorectomy should be counseled regarding the benefits and risks of hormone replacement therapy by the gynecologist prior to surgery. A decision regarding the use of hormone replacement therapy should be possible well in advance of the operation. Good communication between the surgeon and the general practitioner should avoid delays or interruptions in treatment. Counseling about the benefits and possible risks of hormone replacement therapy is particularly important in young women with surgically induced menopause, since these women are at especially high risk of future problems, as discussed above.

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