Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1997-07-08
2001-05-08
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S170000, C514S874000, C514S937000, C424S400000
Reexamination Certificate
active
06228852
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to hormone replacement therapy.
Progesterone is a steroid hormone that is produced by the ovaries during a woman's child-bearing years. Progesterone is also made, although in smaller amounts, by the adrenal glands in both sexes and by the testes in males. An astonishing variety of physiological functions are mediated by progesterone (See e.g., Lee, 1993, Natural Progesterone, BLL Publishing, Sebastopol, Calif.). For example, progesterone, which surges following ovulation, maintains the secretory endometrium and thus, helps to ensure the survival of the embryo and fetus. It also acts as a diuretic, an antidepressant, and as a precursor of corticosteroids and of other sex hormones, notably estrogen and testosterone. There is also evidence that progesterone affords protection against loss of libido, osteoporosis, endometrial cancer, breast cancer, and fibrotic cysts.
When the child-bearing years draw to a close, every woman experiences a decline in the production of progesterone, and consequently, a decline in all of the hormones that are synthesized from progesterone. This decline significantly and negatively affects both life-span and quality of life (Ettinger, 1996, Obst. and Gyne. 87:6-12; Karlberg et al., 1995, Acta. Obstet. Gynecol. Scand. 74:367-372). In addition to the uncomfortable symptoms, such as hot flashes, that are frequently experienced at around the time of menopause, there is an increase in the prevalence of life-threatening conditions, including heart disease, osteoporosis, and brain ischemia (more commonly called a “stroke”; Hunt et al., 1990, Br. J. Obstet. Gynecol. 97:1080-1086). These conditions exact a high personal price and consume significant medical resources. Postmenopausal osteoporosis, the most common metabolic bone disorder in the United States, is the underlying cause of over 1.3 million fractures, at an estimated cost of over $10 billion annually.
Currently, the most common form of treatment for postmenopausal osteoporosis, as well as the other complex physiological conditions associated with menopause, is oral administration of estrogen, either alone or in combination with synthetic progestins. It is estimated that women under the age of 85 who adhere to a program of hormone replacement therapy (HRT) reduce their risk of having a fatal stroke or heart attack by 50-60% (Paganini-Hill et al., 1988, Br. Med. J. 297:519; Henderson et al., 1988, Am. J. Obstet. Gynecol. 159:312). Not only does overall longevity increase (Folsom et al., 1995, Am. J. Public Health 85:1128-1132), but quality of life is improved by HRT as measured by indices of mood, sleep quality, sexual satisfaction, memory, and skin tone, and by bone densimetry (Purdic et al., 1995, Br. J. Obstet. Gynaecol. 102:735-739; Sherwin, 1991, J. Clin. Endocrinol. Metab. 72:336-343; Kimura et al., 1995, Horm. Behav. 29:312-321; Jaliman, 1995, Menopause Mgmt. July/Aug. 34-38; Genant et al., 1989, Am. J. Obst. Gynecol. 161:1842).
There are substantial side effects associated with current hormone replacement therapies (Lee supra; see also Darj, 1992, Maturitas 15:209; Glueck, 1995, J. Lab. Clin. Med. 123:59; Hillard, 1992, Fert. Steril. 58:959-963). For example, administration of unopposed estrogen has been associated with an increased risk of endometrial hyperplasia and adenocarcinoma in women with an intact uterus (Samsioe, 1992, Am. J. Obstet. Gynecol. 166:1980-1985; Ziel et al., 1975, N. Engl. J. Med. 293:1167-1170) and with an increased incidence of breast cancer, regardless of whether or not the patient has had a hysterectomy. Therefore, postmenopausal women who have had breast or endometrial cancer, or who have a strong family history of these cancers, are generally considered poor candidates for many currently prescribed hormone replacements.
Similarly, synthetic progestins are contraindicated for women with known or suspected malignancies of the breast or genital organs, and are associated with a number of undesirable side effects. For example, medroxyprogesterone acetate, a commonly prescribed progestin, carries warnings that it may cause or contribute to pulmonary embolism, cerebral thrombosis, mental depression, nausea, insomnia, fluid retention, migraine headache, renal dysfunction, weight gain, and acne. It is, therefore, not surprising that 30% of the patients for whom HRT is prescribed will never even fill their prescriptions (Ravnikar, 1987, Am. J. Obstet. Gynecol. 156:1332).
In addition to undesirable and potentially lethal side effects, several other factors contribute to the underutilization of HRT world-wide. These include the fear of contracting cancer, the concept that medication is given only to treat illness, rather than to promote wellness, and the related psychological barrier constructed by those who believe that following a program of HRT represents a woman's personal failure to manage her own feminity without chemical intervention.
SUMMARY OF THE INVENTION
The invention features a method of hormone replacement therapy, whereby a combination of native estrogen, native progesterone, and native testosterone are administered transdermally to a patient in need of such therapy. The hormones are synthesized from compounds obtained from a plant source (preferably such as a soybean or yam plant), micronized, and dissolved in a physiologically acceptable cream that can be applied to the skin. Preferably the cream is self-administered to areas of the skin that overlie fatty tissue. Examples of such areas are the lower abdomen and inner thighs. Persons most likely to benefit from the method of the invention are women who are approaching, or who have already come to, the end of their child-bearing years. However, hormone deficiencies caused by events other than menopause can also be treated by the invention.
Preferably, the ratio, by weight, of estrogen to progesterone to testosterone is approximately 1-5 to 10-500 to 1-5, respectively. Most preferably, the ratio, by weight of estrogen to progesterone to testosterone is 1 to 200-250 to 1, most preferably 1 to 250 to 1. The concentration of estrogen in the cream may range from 0.1 to 10 mg/teaspoon, the concentration of progesterone may range from 20 to 2,000 mg/teaspoon, and the concentration of testosterone may range from 0.1 to 10 mg/teaspoon. Preferably, a teaspoon of cream will contain 2-6 mg estrogen, 600-1000 mg progesterone, and 2-6 mg testosterone. More preferably, a teaspoon of cream will contain 4 mg estrogen, 800 mg progesterone, and 4 mg testosterone. The cream may be applied one or more times per day, fourteen or more days per month. Preferably, the site of application is varied.
The invention preferably employs a physiologically acceptable cream consisting of native estrogen, native progesterone, and native testosterone. The cream may also contain an adrenal androgen, such as DHEA (dehydroepiandrosterone), which is produced by the adrenal cortex. A cream that contains native DHEA in addition to the three native sex hormones would be capable of replenishing all of the hormones that normally decline at around the time of menopause.
As described below, considerable confusion has been generated by the improper use of the terms progestin and progesterone in the literature. Herein, and as is correct, progestins are defined as compounds, other than natural progesterone, that are able to sustain the human secretory endometrium.
By “estrogen” is meant any natural substance that induces estrogenic activity. Natural estrogens include estradiol, estrone, and their metabolic product, estriol. The estrogen may be administered as a conjugate i.e., as a sodium salt of the sulfated esters of estrogenic substances.
By “native estrogen, native progesterone, and native testosterone” is meant compounds that are molecularly identical to the estrogen, progesterone, and testosterone molecules naturally produced by the human body.
By “around the time of menopause” is meant at around the time menstruation ceases, which most frequently occurs at the close of the child-bearing years.
Clark & Elbing LLP
Page Thurman K.
Ware T.
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