Hormone replacement therapy monitoring

Details Hormone replacement therapy monitoring Hormone replacement therapy monitoring

1999-09-10

2001-01-16

Leary, Louise N. (Department: 1623)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

C435S975000, C552S502000, C552S605000, C552S607000

Reexamination Certificate

active

06174665

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to methods for monitoring the effectiveness of hormone replacement therapy in various stages of menopause.
BACKGROUND OF THE INVENTION
Menopause is a natural event in a woman's life that designates the end of fertility, and results from decreased ovarian production of estrogen and progesterone. In its strictest sense, menopause refers to a one-day event occurring one year after the last menstrual period. While the majority of women experience “natural” menopause, some women undergo “induced” menopause, due to any one of a number of medical interventions, such as surgical removal of the ovaries, or ovarian damage by radiation or chemotherapy.
Perimenopause refers to a period of up to 7 years wherein the woman has wide fluctuations in estrogen levels from month to month. Perimenopause generally starts when a woman is in her forties, and ends one year after menstruation stops. During perimenopause, a woman may be in estrogen deprivation one month but not the next. She may experience symptoms of menopause, such as hot flashes and insomnia, which also may fluctuate from month to month. During perimenopause, a diagnosis of estrogen deprivation may be accurate one month and proper hormone replacement therapy (“HRT”) prescribed, while the next month the HRT dosage may be too much or not enough.
Early menopause/post-menopause (hereinafter referred to as “early menopause”) refers to the 10-year period starting one year after menstruation ceases, when women are typically in their 50's to early 60's. During early menopause, estrogen levels tend to be consistently low, although lifestyle changes, disease, weight gain or loss exercise increase or decrease, and/or stress may change the optimal HRT dosage.
Late menopause/post menopause (hereinafter referred to as “late menopause”) occurs at age 65 and beyond. Little is known about estrogen metabolism in aged women, and it may differ significantly between a 70 year old and a 90 year old woman. Lifestyle changes, disease, weight gain or loss, exercise increase or decrease, aging, and/or stress may change the optimal HRT dosage, which may decrease in very old women.
The principal circulating estrogen in pre-menopausal women is estradiol-17&bgr;. Estradiol is produced either by direct ovarian secretion or by peripheral conversion of testosterone and estrone.
The predominant estrogen of post-menopausal women is estrone. (Hammond, Climacteric (Chapter 42, pp. 771-790; in Danforth's Obstetrics and Gynecology, 7th edition, ed. Scott et al., JB Lippincott Co., Philadelphia, Pa. (1994). The biological potency of estrone is only one third that of estradiol. The post-menopausal ovary and adrenal gland produce virtually no estrone. Production rates post-menopausally are 40 &mgr;g/day for estrone and 6 &mgr;g/day for estradiol, compared with 80-500 &mgr;g/day for estradiol and 80-300 &mgr;g/day for estrone in reproductive-aged women. (Hammond, 1994)
Virtually all estradiol in post-menopausal women can be accounted for by the conversion of estrone. (Hammond, 1994) Testosterone production in the menopausal woman remains constant, but only about 0.1% of testosterone is converted to estradiol. Testosterone levels in post-menopausal women decline, but not to the same extent as estrogen levels.
Prescription estrogen replacement therapy has been widely used for many years for treating menopause-related disturbances. However, estrogen therapy is still very much a “hit-or-miss” treatment. (See U.S. Pat. No. 5,550,029, incorporated by reference herein in its entirety.) The approach to HRT is routine and empiric. Treatment is initiated with traditional doses, and if the woman does not respond, the dose is increased without evaluating the reason for HRT non-effectiveness. (Notelovitz, Contemporary Ob/Gyn, February 1999 pp. 54-64)
The dosage administered is typically determined based on the results of annual testing, without regard to what stage of menopause a woman is in, and despite the fact that estrogen levels often vary widely from month to month in perimenopausal women. (See for example, Notelovitz, February 1999; Santoro et al., J. Clin. Endocrinol. Metab. 81:1495-1501 (1996). Furthermore, some authorities assert that they “find no need to monitor dosage by any means other than symptoms and bleeding. (From Clinical Gynecological Endocrinology and Infertility, 4th ed., p. 155, Speroff, Glass, and Kase, eds., Williams and Wilkins (MD) 1989) In addition, the HRT protocol may be adversely affected by transient side effects that can be short term (such as nausea or bloating) or long term (such as increased susceptibility to cancer).
Thus, traditional HRT therapy with annual testing is frequently ineffective. As a direct result of this lack of success, it is estimated that only 15% of post-menopausal women currently receive estrogen therapy, and that as many as 80% of women discontinue HRT after initiating treatment. The uncertainty associated with the outcome of long term HRT, as well as the frequent ineffectiveness of treatment, results in unnecessary health care costs, postponement of the potential benefits of alternative treatments such as dietary supplements, and a certain risk of side effects such as increased susceptibility to breast and endometrial cancers, hypertension and gall bladder disease with no actual benefit to offset the risk for the patient. Furthermore, women who respond well to estrogen may be able to benefit from a reduced dosage. There are many types of estrogens on the market and many more in research and development. It is possible that one type of estrogen may be better suited to an individual's needs than another.
The population of postmenopausal is increasing. It is estimated that women in the United States now live approximately one-third of their lives after menopause. Thus, the problems of the perimenopausal, early and late menopausal periods have achieved the status of a major public health concern. (From Clinical Gynecological Endocrinology and Infertility, 4th ed., p. 134, Speroff, Glass, and Kase, eds., Williams and Wilkins (MD) 1989) Estrogen deprivation is associated with many problems, including osteoporosis and increased risk of heart disease.
Therefore, a new approach to evaluate the effectiveness of HRT, which takes into account the menopausal stage and corresponding fluctuation in hormone levels, would have utility in therapy planning by reducing the uncertainty now associated with the outcome of long-term HRT.
SUMMARY OF THE INVENTION
The present invention provides methods for monitoring the effectiveness of hormone replacement therapy in a perimenopausal, early menopausal, or late menopausal woman, comprising testing for hormonal levels in a body fluid of the woman at intervals depending on the stage of menopause, and adjusting levels of replacement hormone administered to the woman based on the test results. In a preferred embodiment, the test is done on saliva.


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Tankersley et al; J. of Applied Physiology, V. 73(4), p. 1238-1245, 1992.
Hammond, Climacteric (Chapter 42, pp. 771-790; in Danforth's Obstetrics and Gynecology, 7th edition, ed. Scott et al., JB Lipincott Co., Philadelphia, PA (1994).
Notelovitz, Contemporary Ob/Gyn, Feb. (1999), pp. 54-64.
Santoro, et al.,(1996), J. Clin. Endocrinol. Metab. 81: pp. 1495-1501.
Clinical Gynecological Endocrinology and Infertility, 4th ed., p. 155, Speroff, Glass, and Kase, eds., Williams and Wilkins (MD) (1989).
Clinical Gynecological Endocrinology and Infertility, 4th ed., p. 134, Speroff, Glass, and Kase, eds., William

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