Talking with your doctor about HRT

Individuals who have had their gonads (ovaries, testes, and/or ovotestes) removed are at increased risk for severe osteoporosis, a serious bone-wasting disease. Some people who have had gonadectomies also report potentially-related symptoms like decrease in libido and increase in skin dryness.

These problems may sometimes be treated or avoided with hormone replacement therapy (HRT). Yet several people have informed us that their doctors are reluctant to give them HRT following gonadectomy because of what they have heard about the Women’s Health Initiative (WHI) study. They mistakenly think the WHI showed that no one should ever employ HRT. If you have had a gonadectomy because of an anomaly of sex development and may benefit from HRT, consider printing the following letter and presenting it to your doctor. Ask her or him to talk with you about HRT, and to consider why your needs may differ from those of the subjects studied in the WHI.

March 30, 2005

Dear colleague:

If you have a patient who has had his or her gonads (ovaries, testes, ovotestes, etc.) removed because of an anomaly in sex development, please consider the importance of providing HRT to that patient.

Why provide HRT?

There are three chief indications for HRT following gonadectomy: (1) initiation of puberty; (2) control of symptoms that affect quality of life; (3) prevention of progressive osteoporosis.

The initiation of puberty is a relatively easy justification for HRT. Because this use is uncontroversial, this letter will not discuss this indication.

HRT is also indicated for patients who have had gonadectomy when they suffer from considerable symptoms attributable to hypogonadism. Hormone replacement is the simplest and surest method of controlling symptoms attributable to a lack of estrogen such as hot flashes, vaginal dryness, as well as changes in skin, mood and libido. Symptom control is, of course, important for a person’s quality of life. It is also important to creating and maintaining a useful and durable patient-physician relationship.

HRT may be used to prevent progressive osteoporosis in patients who have had gonadectomies because of an anomaly in sex development. However, because alternatives to HRT for the treatment of osteoporosis are now available (see below), the use of HRT for the prevention of osteoporosis following gonadectomy remains a thorny issue.

What are the risks and benefits of HRT for patients who have had gonadectomies because of an anomaly in sex development?

The potential sequella of HRT (heart disease, breast cancer, stroke, pulmonary embolism, etc.) in these patients is unknown, as are the long-term potential benefits (reduced fracture rate, colon cancer reduction, quality of life). The reason for the uncertainty is itself pretty clear; there are few if any relevant studies. The use of HRT in patients who have had a gonadectomy because of an anomaly in sex development or in patients who were born without functioning gonads has not been well studied in any age group. There are no randomized controlled trials looking at mortality or morbidity and the observational data is scant. The best evidence has to be drawn from other conditions and the parallels are not complete.

This is the potentially relevant data we can glean from the available studies:

Patients with hypothalamic hypoestrogenic amenorrhea from exercise or weight loss do have low estrogen levels and subsequent losses of bone density. Estrogen has protective effect in the most seriously affected patients in this group (J Clin Endocrinol Metab 1995 Mar; 80(3):898-904). This population, however, has nutritional issues that confound comparison to patients who have had gonadectomy because they had an anomaly of sex development.

One potential comparison population is those patients who have had prophylactic removal of the ovaries due to concern for genetically (BRCA) related ovarian cancer. There are studies that have looked at cancer free survival in these patients who have been placed on replacement estrogen, but there is no data about problems such as osteoporosis stemming from hypogonadism. If data on osteoporosis in these women were published, this would be a good surrogate population for intersex women after gonadectomy with the exception that the women with the BRCA genes are at considerably increased risk of breast cancer than the patients who had gonadectomy related to intersex conditions. The same can be said of adult and pediatric patients who develop hypogonadism after chemotherapy or radiation therapy.

Women who enter menopause particularly early, that is before age 40 years, are often diagnosed with premature ovarian failure. Depending on the age of onset, this population of patients could be a good model for some of our patients who have had a gonadectomy following a sex development anomaly or who had congenital absence of gonads. Unfortunately there is little data to use from this population and many physicians use evidence from the study of postmenopausal women to treat their patients with premature ovarian failure.

This brings us to the most common cause of low estrogen, namely, menopause. In the past HRT was highly touted for the treatment of menopausal symptoms and as a method for preventing heart disease, dementia, osteoporosis and associated fractures, and strokes. Generally, HRT was recommended with only a slight concern about risks of breast cancer and deep vein thrombosis. This was well studied in two randomized controlled trials done as part of the Women’s Health Initiative (WHI). The first found that combination HRT is probably harmful to postmenopausal women. When a combination of an estrogen and a progestin is used, women have an increased risk of coronary heart disease, pulmonary embolism, breast cancer, stroke, and clots in the deep veins. On the positive side these patients have fewer fractures and less colon cancer, but on the whole these women do worse than women not given combination HRT (JAMA 2002; 288(3):321-33).

The second WHI study looked at estrogen used as a single agent in 11,000 women who had had a hysterectomy. This single agent WHI study found that women did decrease hip fracture (6 per 10,000 patient years) on HRT but they had a slightly increased risk of stroke (12 per 10,000 patient years) compared to women who did not receive HRT. The size of the effects was small and the study found no effects on heart disease or breast cancer. One concern with this study is that it also did not show an increase in deep vein blood clots, which would be expected based on previous studies. We don’t know whether the study was inadequate or there is not an increased risk for deep vein clots. (JAMA 2004; 291(14):1701-12)

A third randomized controlled trial called the HERS trial clearly demonstrated that women with coronary heart disease should not take HRT. Interestingly, that study also suggests that HRT does little to help the quality of life and symptoms of low estrogen. (JAMA 2002;287:591-7)

Despite the huge ruckus caused by the WHI and HERS studies, the actual risk of HRT to postmenopausal women is small. For example the risk of heart disease goes up about 0.06% for women taking combination HRT. That means that about 1600 women would have to take HRT to cause one extra case of heart disease. Furthermore, most of the harm to these patients happened in the first year or so after they had taken the medicine and the deleterious effect seems to taper off after that first year. (JAMA 2002;287:591-7)

What alternative treatments are there for osteoporosis?

HRT is no longer typically used as a first line treatment for osteoporosis or for the prevention of osteoporosis in high-risk patients. The bisphosonates (marketed under names like Fosamax, Boniva, and Actonel) are generally recognized as more effective in this regard. Whether these medications would be a better option than HRT for young people with low sex hormones is not clear. One of these medicines, alendronate, is known to be safe and effective over a ten year period, but the long-term safety and effectiveness of other medicines and longer treatment courses are less certain. (NEJM 2004 350(12):1189-99)

So why should HRT be seriously considered?

We realize that the WHI studies combined with the availability of bisphosonates have made many physicians reluctant to offer HRT to women. But the bisphosonates do not address symptoms like vaginal dryness, mood changes, and low libido, and in general the WHI is not applicable to people who have had gonadectomies for reasons of sex development anomalies, because the WHI studies look at older women in their sixties who had a long pre-menopausal exposure to normal levels of estrogen. Moreover, younger people may well need estrogen to maintain their bone density until the age their counterparts would enter menopause. In addition, the risks of HRT seem to be the diseases of older women (except deep vein clots) that should not be encountered in younger women.

As patients get older, however, the issue of replacement hormone therapy will become more difficult. How long should patients who have had a gonadectomy remain on HRT? It is pretty clear that HRT should be stopped when the risk of coronary artery disease, stroke, and breast cancer begin to increase with the accumulation of other risk factors, but how much risk is a debatable point. Likewise it is pretty clear that if a patient develops osteoporosis or is otherwise at high risk of fracture, hormone replacement therapy is not enough and these patients should be placed on more effective treatment that has been shown to prevent vertebral and non-vertebral fractures.

What about HRT for women with a family history of breast cancer?

This is a problem that has been faced for some time by post-menopausal women considering HRT and to a lesser degree by women on oral contraception (higher dose estrogen). For women at low or average risk, breast cancer is not a huge issue. And for women without a uterus, who do not have to take a progestin, breast cancer is an even smaller risk. (Remember that the estrogen-only WHI study did not show an increase in breast cancer.) Still the issue can be vexing, and women with more than one first degree relative (parent, sibling, or child) with breast cancer have about twice the risk of women with no family history of breast cancer. The most evidenced way to go about this decision is to calculate a breast cancer risk for the patient (for example, a Gail score), and if the woman is at high risk, the decision to use HRT should be made after an explicit discussion of risks and benefits with the patient. This decision is best made when the patient gets to weigh the risks (which are rare but bad) and the benefits (which are smaller but perhaps more common).

If HRT is appropriate, what type and level of HRT should be provided?

Recall that there were two WHI studies, one looking at a combination of progestin and estrogen, and the second looking at just estrogen alone. Estrogen on its own is likely to be safer than the combination therapy based on the results of the WHI data.

For women, controlling symptoms attributable to lack of estrogen (hot flashes, vaginal dryness, changes in skin, mood, and libido) does not require the larger dose of hormones used in oral contraceptives. In fact patients may not even require the full dose traditionally used in postmenopausal HRT depending on the patient’s baseline estrogen level.

It is important to remember that even low-dose, unopposed estrogen (that is estrogen used without a progestin as well) can cause endometrial hypertrophy and hyperplasia for patients who have a uterus (which is not always apparent in patients with intersex conditions), and such patients need to use progestin-estrogen combination as their HRT regime.

There are physicians who prefer patients use topical estrogens (patch, cream, suppositories or gel) to the oral versions of HRT. The main argument is that the topical estrogens skip the first-pass liver effect and lead to less estrogen in the liver. This makes some theoretical sense, but the actual evidence that topical administration is more effective (better symptom control or fewer fractures) or safer (fewer blood clots, strokes, or less breast cancer) is hard to come by. Low dose estrogen has similar theoretical benefits, but again there is not convincing data that low dose estrogen is safer or more effective than standard oral replacement. That said, there is generally thought to be a dose-response relationship between estrogen exposure and some known risks like breast cancer. If symptoms are controlled by low dose estrogens, there is no reason to use a higher dose. For patients with local genital symptoms, vaginal creams, suppositories, or rings may be a good option. There is hope that these methods provide local symptom relief without the risks of systemic therapy. Again there is not data to claim that these are indeed safer, but given the low systemic levels of absorption the risk of systemic side effects seems small.

Regardless of the issue of HRT, patients at risk for osteoporosis should be getting 1500 mg of calcium per day through a combination of diet and supplements. Patients should also get 800 IU of vitamin D per day, again through a combination of diet and supplements. Other important lifestyle activities include walking or other weight bearing exercise at least 30 minutes per day 3 times per week, and the avoidance of smoking. The latter cannot be overemphasized since tobacco causes osteoporosis and leads to a significant increase in all of the risks attributed to HRT.

Sincerely,

Aron Sousa, M.D.
Department of Medicine
Division of Internal Medicine
Michigan State University
East Lansing, Michigan

Member of the ISNA Medical Advisory Board

Conflicts of interest: none.