Hormones for the Long Haul - The Jury is Still Out

Safety of the long-term use of menopausal hormone therapy

One of the most significant pivots in the hormone therapy (HT) recommendations that emerged from the North American Menopause Society (NAMS) 2023 Position Statement on Hormone Therapy is the notion that there is no set time when hormone therapy must be discontinued. This is in stark contrast to earlier position statements where a 5-7 year timeline, depending on HT formulation, (estrogen and progestin versus estrogen alone) was suggested. As more studies emerged over the last decade, there has been greater clarification surrounding the safety of HT in different patient populations as well as with different HT formulations. These results led to the decision in the 2023 position statement to continue HT based on an assessment of the benefits weighed against the risks rather than an arbitrary timeline.

When considering the “benefits” of HT, the recommendations set forth by the NAMS position statements include effective treatment of hot flashes, urinary and vaginal symptoms, disease prevention in women with premature menopause, and prevention of osteoporosis.

Through the last decade, the collective data surrounding HT use for the prevention of cardiovascular disease and cognitive decline remain mixed and thus the collective data does not support the use of HT for the sole benefit of disease prevention in women entering peri-menopause/menopause at the typical age according to NAMS.

But what about the woman who initiates HT for hot flashes, as an example, within the first 10 years of menopause onset but wishes to continue HT once the hot flashes resolve? The long-term use of HT continues to be a “gray area” in the medical literature as research has evolved beyond the initial long-term randomized controlled trials (RCTs) of the 1990’s such as the Women’s Health Initiative (WIH) and the Heart and Estrogen / Progestin Replacement Study (HERS).

Today, we will review an article published in the (October 2023) issue of Menopause that is a valuable contribution to the literature speaking to some of the questions surrounding the long-term use of HT.

Benefits for cardiovascular system, bone density, and quality of life of a long-term hormone therapy in hysterectomized women: a 20-year follow-up study

Maria Isabel Lorite, MD, PhD, Angela Maria Cuadros, MD, PhD, Mario Rivera-Izquierdo, MD, PhD, Victoria Sanchez-Martin, PhD, and Marta Cuadros, PhD from Granada, Spain.

Goal of the study

Analyze the effects of 20 years of transdermal estradiol HT in women after hysterectomy, with respect to the symptoms of menopause, blood pressure, lipid profiles, bone density and quality of life.

Study methods

• This was a prospective (forward-looking) observational, longitudinal study of women taking HT.

• Menopausal women who had undergone a hysterectomy (86% for non-cancerous causes and 14% for gynecologic cancers) were managed at the Menopause Medical Unit at Hospital Universitario San Cecilio in Grenada, Spain. Participants were recruited from September 1989 to May 1998 and followed for 20 years. All but 5 women had reached menopause prior to hysterectomy.

• All women were started on an initial transdermal estradiol dose of 0.05 mg/day which continued for 20 years. Once a participant reached age 60, the dose was cut in half.

• Only women who completed the 20-year follow-up, including changes in doses at 60 years of age, were included in the study.

• Clinical data included cardiovascular parameters such as body mass index (BMI), lipid parameters, and systolic and diastolic blood pressure. Bone health metrics included bone mineral density and incidence of fractures. Breast cancer assessment was achieved through mammography and/or sonography. Quality of life metrics including menopause onset, symptom intensity, and lifestyle factors were assessed with the Kupperman Index (A self-reported 11-question survey of menopausal symptoms).

Results

• 259 hysterectomized women were treated with HT. During the 20-year follow-up period, 203 discontinued HT, 95 of whom were due to “misinformation as the main reason”, according to the authors. Other causes of dropout included “age” (median age of 65), heart disease, high blood pressure, 4 diagnoses of breast cancer, and 1 case of stroke. 56 women remained in the study cohort.

• Quality of life: Menopausal symptoms as assessed by the Kupperman Index showed a significant reduction in symptoms/severity after 20 years of HT use as compared to before initiation of HT.

• Cardiovascular health: Average BMI increased from 29 to 31 over the course of the 20-year follow-up period. LDL levels decreased even in older women after halving the HT dosage. Total cholesterol, VLDL levels, and diastolic blood pressure were also significantly decreased.

• Bone health: Significant bone mineral density increases were seen at the t3 follow-up timepoint even after HT doses were reduced. There were no reported fractures. The authors note that this population had a higher BMI, which is known to be protective of bone mineral density.

• Breast cancer risk: 0.02% of women dropped out of the study due to a breast cancer diagnosis. Two women were diagnosed in the first 10 years of follow-up with an average age of 59.5 years and two additional women were diagnosed 14-18 years into the study with an average age of 64. Population-based statistics of breast cancer incidence in Granda, Spain would predict 3 women would develop breast cancer during that time period.

Author’s Discussion and Conclusions

• Cardiovascular risk and bone fractures decreased in the study cohort as defined by favorable trends in diastolic blood pressure, lipid, and bone density parameters, which persisted even after dosage decrease at age 60.

• There was no association with an increased risk of breast cancer as compared to breast cancer incidence predicted in the general population.

• The authors contend that this study provides new data showing a “clinical benefit of prolonged HT in postmenopausal women older than 60 years as a primary preventive therapy for cardiovascular and bone diseases”.

• This data suggests the beneficial effects of long-term transdermal estradiol HT when initiated close to the beginning of menopause and maintained after 6age 60 in women after hysterectomy.

In My Humble Opinion….

• This study, although small (56 women) follows an important array of clinical and quality-of-life parameters in women taking HT for 20 years, which is much longer than most observational studies.

• It is important to note that 203 of the initial 259 discontinued HT use and thus dropped out of the study. The majority of “drop-outs” were due to “age” and “misinformation”, according to the authors. Four cases were due to cardiovascular disease and high blood pressure, and another 4 due to a breast cancer diagnosis. The final analysis was on the 56 women who completed the 20 years of follow-up, effectively “selecting out” the participants who are arguably at the lowest risk for continuing HT. Had this study been done on an “intention to treat” basis (all participants recruited into the study were analyzed regardless of whether they completed the 20 years of treatment), these data may have looked very different.

• The authors profoundly overstate the implications of this study in their statement regarding the “clinical benefit of prolonged HT in postmenopausal women older than 60 years as a primary preventive therapy for cardiovascular and bone diseases”.

  First, this is a very small, observational study of hysterectomized women from a single clinic on estrogen-only HT. To make such a claim would require a much larger, multi-center, randomized control trial that includes estrogen and estrogen/progesterone HT and controls for the many confounders noted by the authors in their statement of the limitations of their study.

  Second, their narrow demographic of hysterecomized women from one center on estrogen alone limits the applicability to the general population of women taking HT.

• To be fair, the Nurse’s Health Study, which was a much larger but prospective longitudinal cohort of hysterectomized women starting after surgery or within 2 years of menopause onset saw similar results to this study with respect to the benefits for cardiovascular risk and bone health.

Clearly, there continues to be no clear consensus. However, this study is a valuable contribution to the literature despite its limitations with its thorough clinical follow-up over 20 years of HT use. The findings of this study are consistent with the NAMS 2023 Position Statement on Hormone Therapy in that it is appropriate and possibly beneficial to continue HT over longer durations if the benefits continue to outweigh the risks.