There are remarkably few absolute (Table Absolute contraindications to hormone replacement therapy) or relative contraindications to hormone replacement therapy (Table Relative contraindications to hormone replacement therapy).

Table Absolute contraindications to hormone replacement therapy

  • Active
  • breast cancer
  • endometrial cancer
  • other estrogen-dependent tumors
  • Acute thromboembolic disorder
  • Acute myocardial infarction
  • Undiagnosed vaginal bleeding
  • Undiagnosed breast mass
  • Severe liver disease
  • Severe cardiac disease

Table Relative contraindications to hormone replacement therapy

  • History of breast cancer, endometrial cancer, liver disease
  • Previous thromboembolic disorder
  • Enlarging uterine fibroids
  • Endometriosis (recurrence)
  • Estrogen-dependent migraine

There are many other contraindications and special precautions to be found on the hormone replacement therapy prescribing data sheets. Usually these are included on the basis of data from studies of the oral contraceptives or from purely theoretical considerations. In the view of most experts hormone replacement therapy is not contraindicated for those conditions listed in Table Conditions no longer considered contraindications to hormone replacement therapy. This view was endorsed by the British Menopause Society in a recent publication.

Table Conditions no longer considered contraindications to hormone replacement therapy

  • Controlled hypertension
  • Coronary heart disease
  • Varicose veins
  • History of superficial thrombophlebitis
  • Otosclerosis
  • Malignant melanoma
  • History of cervical cancer
  • History of ovarian cancer
  • Benign breast disease

Risks of hormone replacement therapy

Breast cancer

The widely discussed possibility that hormone replacement therapy leads to an increase in the risk of breast cancer has been responsible for much of the controversy surrounding the treatment. The data available from observational studies are widely disparate. A recent meta-analysis of 90% of the available world breast cancer data (over 52 700 cases and 108 000 controls) has to a large extent overridden the individual studies and has made counseling women easier. The study has estimated the background risk of breast cancer incidence in 50- to 70-year-old women at 45/1000 women and has shown significant increases in breast cancer incidence among hormone replacement therapy users. However, this increased risk returned to background levels within five years after discontinuation of therapy. The study reported that body mass index is an independent risk factor for breast cancer: the higher the body mass index, the higher the risk. An important but often overlooked finding was that the excess risk of breast cancer attributed to hormone replacement therapy was confined to women with a BMI of less than 25 kg/m2. The two findings above have subsequently been confirmed in another study. The increase in the relative risk of breast cancer with hormone replacement therapy can be calculated for each year of hormone replacement therapy use. It would seem prudent, therefore, to assess both the potential benefit of using hormone replacement therapy and the risk of developing breast cancer in the case of each individual woman. The addition of a progestogen does not decrease the risk of breast cancer and if anything it may lead to slight increase in the risk. Hormone replacement therapy increases the density of the breast tissue and may decrease the sensitivity of screening mammography. The Nurses’ Health Study reported an increase in risk of dying from breast cancer among users in comparison to non-users, but many studies have reported exactly the opposite. It is conceivable that hormone replacement therapy use may lead to lower death rate because (1) women taking hormone replacement therapy may be healthier at the outset, (2) hormone replacement therapy users tend to have lower all-cause mortality than non-users, and (3) breast cancer striking women on hormone replacement therapy may behave differently with less incidence of lymph node involvement and distant spread. The WHI trial had a secondary endpoint, i.e., the incidence of breast cancer. There was a 26% increase (38 versus 30 per 10 000 woman-years) in the hormone replacement therapy group and no difference in the risk of in situ cancer or breast cancer mortality between the groups.

Endometrial hyperplasia and endometrial cancer

Unopposed use of estrogen increases the risk of endometrial hyperplasia and endometrial carcinoma. The longer the duration of treatment and the higher the estrogen dosage, the higher the risk. The incidence of endometrial hyperplasia is 20, 50 and 62% after one, two and three years’ use of 0.625 mg/day of CEE, whereas the background rate of this condition is between 0.5 and 2% a year. Similarly, there is a three- to ten-fold increase in the incidence of endometrial cancer with unopposed estrogen, depending on the duration of use. Sufficient doses of progestogen, given cyclically for 12-14 days, largely eliminate the risk of endometrial hyperplasia and cancer, but there are studies suggesting that the risk is not completely abolished. Continuous combined hormone replacement therapy offers the best endometrial protection and may even decrease the risks of endometrial hyperplasia and carcinoma to below those seen in an untreated population. Therefore, in women with a uterus, progestogens must always be prescribed for at least 12-14 days every month or continuously. Recommended oral doses for endometrial protection in sequential regimens are:

  1. (1) Norethisterone: 0.7-2.5 mg;
  2. (2) Norgestrel: 75-150 mg;
  3. (3) Dydrogesterone: 10-20 mg;
  4. (4) Medroxyprogesterone: 5-10 mg.

Endometrial protection can be achieved by inserting a levonorgestrel-releasing intrauterine device (Mirena) or by intravaginal progesterone administration (Crinone gel). Progesterone pessaries (Cyclogest) and oral micronized progesterone (Utrogestan) can also be used, but are not licensed for this indication in the UK. With monthly sequential hormone replacement therapy, 70-90% of women will have vaginal bleeding, which commonly starts after the ninth day of progestogen and should be no heavier than a normal period. With continuous combined hormone replacement therapy, about 50-80% of women will stop bleeding after 12 months of treatment. Irregular bleeding associated with hormone replacement therapy use is a common cause of anxiety among women and their doctors and often leads to discontinuation of hormone replacement therapy. The initial approach should include assessment of the problem via history taking and clinical examination. Although the causes of vaginal bleeding are numerous (Table Causes of postmenopausal bleeding), in most cases the bleeding is caused by hormone replacement therapy and not by disease, or can be due to poor compliance, altered gastrointestinal absorption or a drug interaction.

Table Causes of postmenopausal bleeding

(1) Malignant lesions

(a) Endometrium

  • cancer
  • endometrial hyperplasia

(b) Other malignancy of the genital tract

  • vagina
  • vulva
  • uterine sarcoma
  • rarely associated with fallopian tube or ovarian cancer

(2) Non-malignant lesions of the genital tract

  • atrophic endometrium, vagina and/or cervix
  • polyps
  • fibroids
  • endometritis, cervicitis
  • vulvar lesions
  • trauma
  • parasitic infections

(3) Other sources of bleeding outside the genital tract

  • urethral (urologic system: urethral cruncle, cystitis, etc.)
  • rectal (and intestinal diseases): hemorrhoids, rectal neoplasm, etc.

When pathology is absent, a change of regimen, medication or dose may be enough to eliminate the problem. However, endometrial assessment is advised if there is:

  1. (1) Heavy withdrawal bleeding;
  2.  (2) Prolonged withdrawal bleeding;
  3. (3) Breakthrough bleeding for two or more consecutive cycles;
  4. (4) Bleeding in women on continuous combined hormone replacement therapy starting after a period of amenorrhea;
  5. (5) Bleeding continuing for six months after starting continuous combined hormone replacement therapy.

Endometrial assessment is by means of vaginal USS and endometrial biopsy, but occasionally hysteroscopy may be necessary. On USS, endometrial thickness, double layer, of 4 mm or less excludes endometrial carcinoma. Endometrial biopsy is an outpatient procedure and commonly used devices are Pipelle and Vabra. Its limitations are that it is a blind procedure, samples between 4 and 40% (Vabra) of the endometrial surface, may miss a polyp and can cause discomfort or pain. Sometimes the procedure is not possible to perform because of pain or tight cervical sclerosis, or does not provide an adequate sample. In those cases, hysteroscopy and dilatation and curettage (D&C) should be considered. For women on sequential therapy, the ultrasound should be performed immediately after the withdrawal bleeding because the endometrial thickness depends on the phase of the therapy. If the ultrasound scan shows an endometrial thickness < 4 mm, further assessment may not be necessary. If the endometrial thickness is > 4 mm, an endometrial biopsy should be performed. Ultrasound is a very good technique for assessing women on continuous combined hormone replacement therapy. Endometrial biopsy in such patients may not yield any sample.

Thromboembolism

The effects of hormone replacement therapy on hemostasis are complex, and recent observational and randomized controlled studies have shown a two- to three-fold increase in risk of venous thromboembolism (VTE) in current users of hormone replacement therapy (Table Hormone replacement therapy and deep venous thrombosis). Deep venous thrombosis (DVT) is the commonest form of VTE and in 10% of cases it may lead to pulmonary embolism (PE). The mortality of PE is 1-2%.

Table Hormone replacement therapy and deep venous thrombosis

Risk Non-users Users
RR for DVT 1.0 2.1-3.6
RR for PE 1.0 2.1
Absolute for DVT 9-13/100 000 26-35/100 000
Absolute for PE < 1/100 000 2-3/100 000

RR, relative risk; PE, pulmonary embolism

A substantial proportion of thromboembolic episodes occur in women with disorders of coagulation, for example deficiency of antithrombin, protein C or protein S, APC resistance/Factor V Leiden, or G20210A pro thro mbin gene mutation. These conditions tend to run in families and are known as familial thrombophilias. The prevalence of thrombophilia in healthy individuals and in those with VTE is summarized in Table Prevalence of thrombophilia in healthy individuals and those with venous thromboembolism.

Table Prevalence of thrombophilia in healthy individuals and those with venous thromboembolism (VTE)

Thrombophilia factor Prevalence in healthy population(%) Prevalence in patients with VTE(%) RR of thrombosis if thrombophilia factor present
Factor V Leiden 5 40 5
Prothrombin G 20210Agene mutation 3 6-16 2-5
Protein S deficiency 2 4 2
Protein C deficiency 0.3 3-5 >10
Antithrombin deficiency 0.02 1 25-50

If there are historic features suggestive of thrombophilias (Table Features suggestive of familial thrombophilia), a coagulation screen should be performed before prescribing hormone replacement therapy. In women with thrombophilia, hormone replacement therapy is contraindicated. In cases where long immobilization is expected, such as fracture or peri-operatively, hormone replacement therapy needs to be terminated. In cases of long distance travel the standard advice is to keep well hydrated, move around or exercise the legs frequently and wear compressive hosiery.

Table Features suggestive of familial thrombophilia

  • Family history of VTE
  • First episode at an early age (< 45 years)
  • Recurrent VTE
  • Unusual site of thrombosis, e.g., cerebral, mesenteric
  • Thrombosis during pregnancy or puerperium or use of COC or F1RT
  • Spontaneous venous thrombosis without environmental or acquired risk factor
  • Recurrent superficial thrombophlebitis
  • Pulmonary embolism
  • Unexplained stillbirth
  • Unexplained spontaneous abortions (> 3)

VTE, venous thromboembolism; COC, combined oral contraceptive; HRT, hormone replacement therapy

Hormone replacement therapy and endometriosis

Women with a history of endometriosis often require extensive counseling regarding the risk of recurrence with hormone replacement therapy. They may be reassured that such a risk is mainly theoretical and rather remote. Indeed, the current accepted medical treatment for endometriosis is LHRH analogs with add-back hormone replacement therapy.

Hormone replacement therapy and fibroids

There is a theoretical possibility that hormone replacement therapy may lead to enlargement of fibroids, because they are hormone- and, especially, estrogen-dependent. Evidence for this fact is that fibroids commonly enlarge during pregnancy and that treatment of fibroids with LHRH analogs is effective and is often practiced before surgical intervention. However, we have not found this to be a problem and in our clinic we reassure women that hormone replacement therapy is unlikely to lead to recurrence or enlargement of fibroids. We recommend that fibroids are monitored by USS, twice in the first year of hormone replacement therapy and then yearly.

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