Perimenopause, rather than a time of declining estrogen, is characterized by three major hormonal changes that may begin in regularly menstruating women in their mid-thirties: erratically higher estradiol levels, decreased progesterone levels (in normally ovulatory, short luteal phase or anovulatory cycles), and disturbed ovarian-pituitary-hypothalamic feedback relationships. Recent data show that approximately a third of all perimenopausal cycles have a major surge in estradiol occurring de novo during the luteal phase. This phenomenon, named "luteal out of phase (LOOP)" event, may explain a large proportion of symptoms and signs for symptomatic perimenopausal women. Large urinary hormone data-sets from women studied yearly over a number of years in the Study of Women Across the Nation (SWAN) and in the Tremin data will eventually provide a more clear prospective understanding of within-woman hormonal changes. Predicting menopause proximity with FSH or Inhibin B levels is documented to be ineffective. Anti-Mullerian hormone levels may prove predictive. Finally, there is an urgent need to change perimenopause understandings, language and therapies used for midlife women's symptoms to reflect these hormonal changes.
Prior JC perimenopause endocrinology paradigm shift, perimenopause estradiol progesterone ovulatory disturbances, luteal out of phase LOOP event perimenopause, erratically higher estradiol perimenopause ovarian-pituitary feedback, perimenopause anovulatory cycles short luteal phase progesterone decline, FSH inhibin B anti-Mullerian hormone menopause prediction, SWAN study perimenopausal hormonal changes prospective, perimenopause estrogen excess progesterone deficiency symptoms, midlife women hormonal changes menstrual cycle ovulation, perimenopausal luteal phase estradiol surge de novo
PMID 21196391 21196391 DOI 10.2741/s166 10.2741/s166 Jerilynn Prior et al. 2011, Jerilynn Prior 2011
Cite this article
Jerilynn C Prior, & Christine L Hitchcock (2011). The endocrinology of perimenopause: need for a paradigm shift. Frontiers in bioscience (Scholar edition), 3(2), 474-486. https://doi.org/10.2741/s166
Jerilynn C Prior, Christine L Hitchcock. The endocrinology of perimenopause: need for a paradigm shift. Front Biosci (Schol Ed). 2011;3(2):474-486. doi:10.2741/s166
Jerilynn C Prior, and Christine L Hitchcock. "The endocrinology of perimenopause: need for a paradigm shift." Frontiers in bioscience (Scholar edition), vol. 3, no. 2, 2011, pp. 474-486.
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To the Editor: In their recent article, "Characterization of Perimenopausal Bone Loss," Recker and colleagues present unique longitudinal bone mineral density (BMD) and hormonal data.1 We acknowledge the work involved in recruiting, motivating, and continuing to follow 75 women each for an average of 8 years. The data from this study are an important contribution to our knowledge of bone changes through the natural perimenopausal transition. Unfortunately, these authors have chosen to reduce the complex endocrinological and physiological changes of perimenopause2 to one idea—"estrogen deprivation." Our first concern is that "estrogen deprivation" or "depletion" is not an adequate concept with which to explain the rapid bone loss during perimenopause. The author's own data show that 50% of spinal BMD loss has occurred by 6 months before the final menstrual period at which time estradiol levels are not lower than in the so called "estrogen replete" group. In this study, perimenopausal bone loss appears to begin approximately 3 years before the final menstrual flow, which is about the time when menstrual cycles become irregular.3 Several other studies also show accelerated rates of perimenopausal bone loss.2, 4, 5 During these later phases of perimenopause, estradiol levels can be very high and certainly are not consistently low.2, 6, 7 If estradiol levels are not low in perimenopause, how can we explain the rapid bone loss? First, estradiol levels vary widely.2 Perhaps, acute drops in estradiol levels (often from abnormally high values) cause increased bone resorption much like that which has been shown to occur within seven days of premenopausal ovariectomy.8 A second possibility is that perimenopause causes psychosocial stress.9 Social stress coupled with high estradiol levels in men have been experimentally shown to cause increased cortisol levels10 that are known to be negative for bone. Finally, ovulatory changes that increase as women progress through perimenopause,11 are associated with accelerated cancellous bone loss, despite normal estradiol levels and regular cycles in premenopausal women.12 Replacement of luteal phases with cyclic progestin in a double-blind randomized study in premenopausal women with abnormal cycles caused an important positive change in spinal BMD.13 As a mechanism to allow use of all of their data, the authors labeled "estrogen replete" those women who continued to menstruate as well as those who started hormone therapy before menopause. It seems odd to us to combine data from three women who have undergone ovariectomy and seven women on exogenous hormone therapy with 10 preor perimenopausal women. The estrogen deprivation hypothesis has led the authors to overlook important physiological differences within this group. We request that the data for the 10 untreated preor perimenopausal women be provided and that we be told whether or not they continued to menstruate regularly. In women's life cycle, low levels of estrogen are as natural for menopausal women as for toddlers. To label menopause as a hormone deficiency condition is to ignore the normal hormonal pattern of women's lives. Recker and colleagues suggest that "hormone replacement therapy" should "begin as early as 2 years before the last menstrual period." Although we acknowledge that vasomotor symptoms commonly begin in perimenopause and have a very negative impact on quality of life, we suggest that progesterone would be a more appropriate therapy. Progesterone is truly low at this phase of perimenopause11 and is effective for night sweats/hot flushes. We fear that prescription of estrogen to women in late perimenopause may have negative consequences in both the short and the long-term. In the short term, it may exacerbate symptoms such as breast tenderness, headaches, and fluid retention. In the long term, having experienced side effects from estrogen treatment these women may refuse it when they are menopausal, a time when it has the potential to be valuable therapy. In summary, this important study is flawed because it relies on a clearly inadequate "estrogen deprivation" concept as the sole explanation for differences found in the prospective data from midlife women.