Recurrent Vasomotor Symptoms Following the Discontinuation of Postmenopausal Hormone Therapy

August 2005

 Two recent articles in the Journal of the American Medical Association bring much-needed attention to an increasingly common clinical scenario: the recurrence of menopausal symptoms after discontinuation of postmenopausal hormone therapy (HT). These articles underscore the need for clinicians to regularly follow-up with patients experiencing menopausal symptoms and to carefully evaluate each patient's unique needs in the context of evolving data on the risks and benefits of HT.

In the April 13, 2005 issue of Clinical Crossroads, an article provided follow-up on the case of a now 62-year-old woman who suffered severe hot flushes following her attempt two years ago to discontinue unopposed estrogen therapy.¹ She had used estrogen therapy for symptom relief since undergoing hysterectomy and bilateral salpingo-oophorectomy at the age of 40 years. Her decision to discontinue HT after 20 years of use was based on her "increasing level of concern about her family history of breast cancer and the risks of HT that she had been reading about in the lay press."² Although this patient reported that it was very difficult to tolerate the symptoms that she encountered in her attempt to discontinue HT, she was advised to again try to taper her estrogen although over a more extended period of time. The rationale for this advice was "growing concerns about the potentially increased risk of breast cancer risk and coronary events in users of hormone therapy based on the Heart and Estrogen/Progestin Replacement Study, other published randomized trials, and early reports from the Women's Health Initiative."²

In this follow-up two years later,¹ we learn that, over a one-year period, the patient tapered first to a daily low dose and then gradually tapered to every other and then every third day before stopping HT. However, she still reports hot flushes that are difficult to tolerate. At the same time, she is frightened to resume HT:

 

"I am off the hormone therapy completely now...I know my life would be so much easier if I still took it. I felt so good when I was on it. I shouldn't have taken it, but I did what I thought was right at the time...I don't know how much damage I've caused to my body. I have to deal with that now. The hot flashes are quite frequent. I have the hot flashes every hour. They last 2 to 3 minutes...I don't wish this on my worst enemy. It takes a great deal of willpower to stay off the estrogen, but I keep telling myself I should. I tried soy, but that did nothing. Someone mentioned herbal things, but I just don't feel like trying new things when I am taking other medication...I don't know what the next step is. There really isn't guidance out there; people out there are just guessing. If the doctors and the researchers can realize that it's a true suffering, it's not just "she'll get over it"-it's not like that. It really makes an impact on your personal life. I'm standing here right now just dripping. It just pulls you down, especially as you get older. Women don't need this on top of everything else. I would like to feel the best I possibly can. I want to get the most out of life and enjoy my family."

Clearly, this patient's words reveal how uncomfortable and guilty she feels, and how desperate she is to obtain relief. Data published in 2004 from the WHI on the risks and benefits of unopposed estrogen therapy³ are especially relevant for this patient and the results should be shared with her at this 2-year follow-up. These results from the WHI estrogen-alone clinical trial are based on outcomes from nearly 12,000 women with prior hysterectomy who were randomized to receive either conjugated equine estrogens (CEE) or placebo. After a median 6.8 years of unopposed estrogen therapy, there was no increased risk of cardiovascular events and a trend towards a reduction in the risk of breast cancer that just failed to reach statistical significance. An increased risk of stroke was, however, associated with the use of unopposed estrogen. Carefully reviewing the results of the WHI estrogen-alone trial with this patient and relating the findings to her needs enables the physician to reassure her, offer immediate relief of symptoms, and assuage her guilt. This distraught woman could find solace and comfort and safely return to HT by clarification of her risks and benefits in view of the most current and relevant scientific evidence. Of course, this patient may consider the evidence and decide not to re-start HT, but her decision must be based on an accurate and comprehensive understanding of the risks and benefits of treating her menopausal symptoms with unopposed estrogen.

Patients such as this one who experience recurrent symptoms following discontinuation of HT are common, yet research is lacking on the prevalence, severity, and duration of these recurrent symptoms. Recently, women who had participated in the WHI estrogen plus progestin (E+P) clinical trial were surveyed about the symptoms they experienced after discontinuing their study medication (HT or placebo) when the study was stopped prematurely. The results of this survey, which was sent only to those women who were still taking study medication at the trial stop date, were published in the July 13, 2005 issue of JAMA.⁴ The survey found that 21% of the women who had been using E+P therapy during the trial reported moderate or severe vasomotor symptoms after discontinuing treatment. However, the rate of recurrent symptoms was substantially higher in the subset of women who were experiencing menopausal symptoms at the outset of the clinical trial-more than half of these women (55.5%) reported moderate or severe vasomotor symptoms after discontinuing HT. Interestingly, 5% of the women who had been on placebo during the trial reported moderate or severe vasomotor symptoms in the year following the trial stop date. As seen in the E+P group, being symptomatic prior to entering the clinical trial increased the likelihood of recurrent symptoms among the women in the placebo group. Unclear from these findings is whether the women in the placebo group who reported symptoms after the trial ended had also experienced symptoms during the trial or whether these women were more likely to be among the 11% of women who "crossed over" during the trial and initiated HT with their own physician. Thus, although these findings were dubbed the "placebo withdrawal effect" in a related editorial,⁵ other plausible explanations should be considered as well.

Certainly, the average age of the WHI participants (69.1 years at the time the E+P study was stopped) and the small proportion of the WHI study population reporting menopausal symptoms at baseline limits the applicability of the survey's findings to the population of younger, symptomatic postmenopausal women most likely to receive treatment with HT. Despite these limitations, the study addresses an important clinical issue and provides information of value to practitioners. In the small group of women aged 55-59 years (n=598), the rate of recurrent hot flushes or night sweats after discontinuing E+P was 36%. Although not reported, the rate of recurrent symptoms was likely higher among women aged 55-59 years who reported menopausal symptoms prior to the start of the trial. While further research is needed to more accurately estimate prevalence of recurrent symptoms in younger, symptomatic postmenopausal women, current evidence suggests at least one-third to one-half of these women can be expected to experience recurrent symptoms when HT is discontinued. Further research is also needed on the average duration of recurrent symptoms, the effects of various discontinuation strategies (eg, using lower doses, decreasing the number of days per week that HT is taken, or a combination of these strategies), and the usefulness of lifestyle strategies to manage recurrent symptoms (eg, drink more fluids, wear layered clothing). In the WHI survey, women with recurrent symptoms reported trying a number of lifestyle strategies to manage their symptoms and most women felt these strategies were "helpful." Interpretation of this finding is difficult, however, as the questionnaire gave respondents only three responses ranging from "helpful" to "made things worse" to describe their perceptions of these strategies.⁴

In conclusion, the WHI investigators and the editors at JAMA are to be commended for facilitating scientific and clinical discourse on the recurrence of menopausal symptoms after HT discontinuation. The recent publications in JAMA provide an opportunity to remind clinicians that current recommendations for the use of HT are not simply to use the lowest effective dose for the shortest duration possible, but rather to use the lowest effective dose for the shortest duration needed to reach therapeutic goals.^6,7 For the woman who continues to have disruptive vasomotor symptoms, therapeutic goals are not being met and the potential re-initiation of HT should be re-evaluated within the context of the risks and benefits for this individual patient.

Lila Nachtigall, M.D.
Professor of Obstetrics and Gynecology
New York University School of Medicine
530 First Avenue, New York, NY 10016


 

1. Reynolds EE. A 60-year-old woman trying to discontinue hormone replacement therapy, 2 years later. JAMA. 2005;293:1780.
2. Grady D. A 60-year-old woman trying to discontinue hormone replacement therapy. JAMA. 2002;287:2130-2137.
3. Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291:1701-1712.
4. Ockene JK, Barad DH, Cochrane BB, et al. Symptom experience after discontinuing use of estrogen plus progestin. JAMA. 2005;294:183-193.
5. Petitti DB. Some surprises, some answers, and more questions about hormone therapy: further findings from the Women's Health Initiative. JAMA. 2005;294:245-246.
6. American College of Obstetricians and Gynecologists. Hormone Therapy. American College of Obstetrics and Gynecologists. 2004;104:1S-131S.
7. North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause. 2004;11:11-33.

 

• HRT and ERT may improve mood and psychological well-being.

Con

• ERT, especially without the use of a progestin, increases the risk of cancer of the uterus (endometrial cancer).
• HRT can have unpleasant side effects, such as bloating or irritability.
• HRT and ERT may increase risk of breast cancer; long-term use may pose the greatest risk.
• In women at risk of blood clots, HRT and ERT may be dangerous.