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EDITORIAL |
Chief Scientific Officer Ligand Pharmaceuticals, Inc. San Diego, California
At the threshold of our transition into the new millennium, women’s health issues, concerns, and new knowledge are, finally, coming of age. Remarkable changes in both socioeconomical conditions affecting women and biological parameters impacted by changes in life expectancy have radically changed women’s lives and expectations during this century. A woman living at the end of the 19th century had a projected life span barely exceeding 50 yr. At the end of the 20th century, women in developed countries have life expectancies well exceeding 80 yr. That means that in less than 100 yr the amount of time that a woman will live after the menopause has increased from less than 5 yr to more than 30, or about 40% of the projected life span. Concurrent with these demographic changes, a wealth of information derived from basic, clinical and epidemiological research has increased our awareness of areas such as osteoporosis, cardiovascular disease, and cognitive disorders, including Alzheimer’s dementia, as major factors affecting women’s health and the role that hormone deficiency plays in contributing to those disorders.
The information accumulated in all the above areas eventually resulted in a progressive change in attitude, focus and level-of-effort dedicated to women’s health research. Endocrinologists, and I use the word in a broad sense here to include all basic and clinical scientists from different disciplines that study the role of the endocrine system in women’s health disorders, have played a major role in leading those efforts. Their contributions have provided approaches and therapies to not only treat but also prevent major disabling diseases and, to a large degree, to enhance quality of life of women throughout their lives.
The authoritative reviews contained in this special issue of Endocrine Reviews are a clear testament to the seminal contributions that endocrinologists have made in this field. From basic mechanisms of hormone action, to animal models that reproduce estrogen deficiency using classical or transgenic approaches, to novel therapeutic methods to treat or prevent osteoporosis, cardiovascular disease, infertility, and breast cancer, the articles in this issue provide a compendium of information that summarize the most important advances in this field over the last two decades. Many of these advances already translate into new treatments or new approaches to treatment that will benefit women well into the next millennium. Other basic concepts provide hope for even more promising ways to diagnose, treat, and/or prevent diseases that particularly affect women, such as neurodegenerative disorders, autoimmune diseases, and breast, ovarian, uterine, and cervical cancer.
Our knowledge on the molecular biology of the steroid receptors has
experienced explosive growth in the last decade and has clearly opened
the way to a better understanding of the role that steroid hormones,
such as estrogen and progesterone and many therapeutic agents
containing natural or synthetic estrogens and progestins, play in
maintaining the integrity and function of the body’s major organs or
systems, not only during development, but also during adult life and
into senescence. The article by McKenna, Lanz, and O’Malley provides a
lucid and complete update of the cellular and molecular biology of
nuclear receptor coregulators, an ever-expanding family of proteins
that integrate the nuclear receptor complex and play an integral role
in defining the genomic responses elicited by agonists, partial
agonists, or antagonists, as well as contributing to the profile of
tissue selectivity that is central to the concept of selective steroid
receptor modulators. This article is complemented by an excellent
review by Couse and Korach on the biology of estrogen receptor-null
mice, an exciting approach to dissect the contribution of either
estrogen receptor subtype (
or ß) or both to the biology of each
major tissue. Much has been learned recently from these valuable animal
models, and this information is quite useful, when combined with other
molecular, cell biology, and pharmacological approaches to provide a
detailed picture of the contribution of each estrogen receptor subtype
and of ligands specific to those receptors to selective tissue growth,
differentiation, and function. This information is also central to
guiding current and future efforts in the development of novel SERMs
(selective estrogen receptor modulators) to expand the range of
therapeutic opportunities in hormone replacement therapy. The chapter
by Suda and colleagues expands our current information base on
osteoclast differentiation and function, an active and important area
of research that focuses on the key regulatory mechanisms and factors
contributing to bone formation and remodeling.
Wise and colleagues present a clear and concise view of the neuroendocrine changes that precede or accompany the menopause. McEwen and Alves’ review masterfully addresses estrogen’s actions in the central nervous system, providing a thorough and compelling picture of the importance of steroids, such as estrogens, progesterone, and glucocorticoids, in developing and maintaining brain function at both autonomic and cognitive levels.
Four articles are dedicated to clinical and therapeutic approaches to women’s health disorders. The paper by Jordan and Morrow describes the pioneering work of Jordan’s laboratory, as well as others, in bringing tamoxifen to the forefront of breast cancer treatment and prevention. This represents one of the major advances at the end of this century in the field of women’s health, by providing not only a means to treat, but also to prevent this terrible disease and, in addition, by providing key initial proof-of-concept in the clinic that stimulated the development of current and future SERMs. Cosman and Lindsay expand on this concept by reviewing the most current information on SERMs presently tested in the clinic. Separation of bone and cardioprotective activity from a negative impact in breast and uterus is now a reality for novel SERMs, although the magnitude and extent of the protective effects is still being elucidated. A feature still to be conquered relates to the development of a novel SERM that also has positive effects on brain function, including suppression of vasomotor symptoms in postmenopausal women, improvement of mood and cognitive function, and possible protection against neurodegenerative disorders, such as Alzheimer’s disease. Clinical evidence of estrogens with selectivity for neuroendocrine and other central nervous system effects, as well as other selected peripheral effects, such as bone protection, has recently been published (1), increasing our hope that indeed it will be possible to develop an ideal or nearly ideal SERM that captures all the key beneficial elements desired.
While these approaches are perfected and the novel SERMs are developed and evaluated, other drugs that address specific disorders (i.e., osteoporosis, dyslipidemia) or different delivery systems are potential alternatives to estrogen replacement, as evaluated by Pinkerton and Santen. Finally, Barbieri and Hornstein review succinctly more refined treatment protocols applied to the field of assisted reproduction, an area that over the last 20 yr has experienced a revolution in our approaches to the treatment of infertility, bringing new hope to the many couples affected by this common dysfunction.
References
8,9 dehydroestrone sulfate in postmenopausal women.
J Clin Endocrinol Metab 84:2020–2027This article has been cited by other articles:
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  S. Nilsson, S. Makela, E. Treuter, M. Tujague, J. Thomsen, G. Andersson, E. Enmark, K. Pettersson, M. Warner, and J.-A. Gustafsson Mechanisms of Estrogen Action Physiol Rev, October 1, 2001; 81(4): 1535 - 1565. [Abstract] [Full Text] [PDF]
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