The Menopause Transition: Interview with Ellen W Freeman

Ellen W Freeman is a Research Professor in the Department of Obstetrics/Gynecology and the Department of Psychiatry at the University of Pennsylvania School of Medicine in Philadelphia (PA, USA). She directs the PMS research program and is co-director of the Human Behavior and Reproduction unit in the Department of Obstetrics and Gynecology. She received her AB in history in Smith College in Northampton, Massachusetts and her MS and PhD in social research from Bryn Mawr College in Bryn Mawr, Pennsylvania. She has published more than 200 scientific articles, book chapters, reviews and abstracts on premenstrual syndromes, perimenopause, adolescent pregnancy, infertility and related topics as well as a book on teenage pregnancy. In addition, she has lectured extensively worldwide on mood disorders and menopause in women. She is also a member of the editorial boards of Medscape, Archives of Women's Mental Health and Mental Fitness: Psychiatry, OB/GYN, Primary Care and is a Fellow in the College of Physicians of Philadelphia.

Q Dr Freeman, you are a Research Professor in the Department of Obstetrics/Gynecology at the University of Pennsylvania School of Medicine (USA), directing the Human Behavior and Reproduction Unit. Can you tell our readers a little about how you became involved in this field? What do you think are your (& your team's) greatest career successes to date?

My interests have always centered on women's reproductive issues. The trajectory followed a natural sequence of events in women's reproductive life, and was supported by timing and luck! For example, I started with issues of unwanted pregnancy, then followed teenage pregnancy, which was a targeted priority of the National Institutes of Health with considerable research funding at the time. Following that, I moved into mood and behavioral issues in infertility, which then morphed into menstrual cycle problems. The timing coincided with a renewed interest among clinical researchers in premenstrual syndromes, where the scientific impetus was to define diagnostic criteria and identify the efficacy of treatments for this disorder. With the normal aging of this patient population, the focus shifted to menopausal symptoms. My research addressed questions about the development of menopausal symptoms and their duration in the general population. Overall, our research has contributed to better understanding of mood disorders associated with the menstrual cycle and has demonstrated efficacy of treatments for the disorders in randomized, placebo-controlled clinical trials. Our team has also contributed new information about menopausal symptoms, their prevalence among midlife women and their associations with health problems.

Q Today, we are focusing our interview on the menopause transition; can you talk a little about symptom prevalence around the menopause?

Women's experiences and clinical wisdom traditionally have considered menopause as a time associated with new or worsening mood, behavioral and physical symptoms. More recent perspectives have emphasized that menopause is a natural and universal occurrence that does not mark the onset of debilitating symptoms for most women. Nonetheless, increasing evidence indicates that symptoms such as vasomotor symptoms (VMS), depressive symptoms and sleep difficulties are more prevalent in the transition to menopause when compared with the preceding reproductive years. However, the evidence that these symptoms are due to the changes of ovarian aging is mixed. Disentangling the effects of menopause from the effects of aging more broadly continues to be needed.

The most frequently reported symptoms around menopause are the VMS (hot flashes, night sweats), which are experienced by more than 80% of midlife women. There is great variability in the severity, time of onset and duration of VMS; many women report little bother while others are debilitated by the symptoms. Other commonly reported menopausal symptoms include depressed mood, poor sleep, decreased libido, cognitive difficulties, particularly memory complaints, vaginal dryness and associated sexual difficulties. These symptoms may be occurring in association with other physical effects of aging more than the ovarian decline specifically, but the causes are complex and not clearly understood at this time.

Q Some of your work has highlighted the link between the menopause transition & the onset of depressive mood or even depressive disorders. Can you tell us about your research in this area?

We have focused on associations of depressive symptoms and clinical depression with the menopause transition in a population-based cohort of midlife women. Our findings have added important information about increases in these symptoms and their associations with changes in reproductive hormones, particularly as women enter the transition period. We have also clearly demonstrated the impact of a history of depression, which accounts for more of the depressed mood around menopause than first-onset depression. More recently, we have shown the pivotal point of the final menstrual period; here, depressive symptoms overall were higher before this point and decreased following the final menstrual period. Women with a history of depression had a significantly greater risk of depressed mood at all rime periods compared with women with first-onset of depressed mood. While we and others have provided evidence that supports the role of the changing endocrine milieu in the development of depressed mood, the contribution of hormones as measured in these studies is small. Disentangling the numerous factors that are associated with depression in midlife women continues to be a major challenge for research and for clinical care.

Q How have your findings regarding depressive symptoms affected management of menopause, if at all?

We like to think that our research informs medical management of menopause by showing the complexity of menopausal symptoms, the importance of treating these symptoms when they are distressing and the need to investigate further when symptoms are not solely attributed to the changing hormonal milieu. Our research indicates the importance of evaluating whether symptoms are due to other disorders (such as episodic or chronic depression or poor sleep that predates the menopause transition) and are not simply due to hormonal changes of menopause. Symptom management needs to be directed to the most debilitating symptoms, which may not be ‘menopausal’ symptoms but due to other disorders. Furthermore, we hope that our findings reach women in order to increase understanding of menopause, the great variability of symptoms and the diversity of approaches to symptom management.

Q Your team have also reported on correlations between hormone levels & menopausal symptoms. Can you tell our readers about any interesting findings you have reported from research in this area? Again, has this research affected management of menopause?

Our working hypothesis is that changes or fluctuations in reproductive hormone levels are associated with menopausal symptoms. We have reported that increased estradiol was association with depressive symptoms adjusted for history of depression, race and age with subject aggregate profiles in the menopause transition in our cohort. This possibly reflects the fluctuations in estradiol that occur in the late reproductive years, when estradiol increases due to the changes in ovarian production before it finally decreases to postmenopausal levels. We have also reported significant changes in other reproductive hormones (e.g., follicle-stimulating hormone, inhibin b and luteinizing hormone) with the onset of depressed mood among women with no history of depression. These biologic changes do not fully account for symptoms but interact with other physical, psychological and psychosocial characteristics.

Q How has menopause symptom management changed in general over the last 5 years, & in what direction do you think the field is headed over the next 5 years?

Menopause management has been greatly affected by the results of the Women's Health Initiative, which reported strong negative findings for the use of hormone replacement therapy. A result was that HRT use, which was long the first-line treatment for menopausal symptoms, decreased by nearly two-thirds in the USA. With the concerns of women and clinicians for the use of HRT, which was the only pharmacologic treatment approved by the US FDA for menopausal symptoms until recently, women turned to alternative treatments such as herbal medicines and dietary supplements. Many women experience improvement with these treatments, but scientific evidence for their efficacy remains elusive. Although the FDA recently approved a serotonergic antidepressant for menopausal hot flashes, both clinicians and women have been reluctant to use these nonhormonal treatments for menopause management. The thrust of investigations in the next 5 years is toward identifying the efficacy of the ‘lowest possible dose’ of estrogen and identifying efficacy for other nonhormonal approaches.

Q Are there any new treatments in the pipeline that might enable more effective management while minimizing side-effect profiles?

Recent clinical trials identified efficacy for nonhormonal treatments including serotonergic antidepressants (escitalopram, venlafaxine) and slow-release gabapentin. The side-effect profiles in these trials were low and did not exceed placebo. These treatments appear to be effective at low doses for menopausal hot flashes and offer alternatives for women who cannot or do not wish to use estradiol. Conjugated estrogens/bazedoxifene (an SERM rather than progestin) is another recently approved option with low side-effect profiles.

Q What are the main obstacles that the field faces with regard to effective symptom management?

Many menopausal symptoms are nonspecific and most are multifactorial. While HRT was long considered the treatment for ‘menopausal symptoms’, we now see that hormone therapy is effective for some but not all symptoms and that the recommendations are for time-limited use, which may not be sufficient for all symptoms. It appears that the majority of women who use hormone therapy experience return of symptoms, particularly hot flashes, when they discontinue the therapy. Clinicians are challenged to determine whether symptoms are primarily associated with the menopause transition – and are thus likely to be time-limited – or whether the symptoms represent underlying medical or psychiatric illnesses. This requires that clinicians have a wide understanding of changes that occur in the menopause transition in order to maximize women's health and well-being.

Q What research do you (& your teams) have in the pipeline? Anything exciting to tell our readers about?

The current aims of research in our cohort of midlife women have shifted to investigation of the role of childhood adversity in the manifestation of depressive symptoms.

Disclaimer

The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Future Medicine Ltd.