Treatment of hot flushes, vasomotor symptoms, and night sweats with sex steroid precursors in combination with selective estrogen receptor modulators

Abstract

Novel methods for reduction or elimination the incidence of hot flushes, vasomotor symptoms, and night sweats while decreasing the risk of acquiring breast, uterine or endometrial cancer and furthermore having beneficial effect by inhibiting the development of osteoporosis, hypercholesterolemia, hyperlipidemia, atherosclerosis, hypertension, insulin resistance, diabetes type 2, loss of muscle mass, adiposity, Alzheimer's disease, loss of cognition, loss of memory, or vaginal dryness in susceptible warm-blooded animals including humans involving administration of an amount of a sex steroid precursor, particularly dehydroepiandrosterone (DHEA) and an antiestrogen or a selective estrogen receptor modulator, particularly compounds having the general structure:

Pharmaceutical compositions for delivery of active ingredient(s) and kit(s) useful to the invention are also disclosed.

Description

CROSS REFERENCE TO RELATED APPLICATION(S)[0001]The present application claims priority under 35 U.S.C. §119 of U.S. Provisional Application 61 / 187,549 filed Jun. 16, 2009, the contents of which are all incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to a new treatment for hot flushes, vasomotor symptoms, and night sweats in women. In particular, the treatment includes the administration of a precursor of sex steroids in combination with a selective estrogen receptor modulator (SERM) for reducing the risk of acquiring breast or endometrial cancer. The invention also provides kits and pharmaceutical compositions for practicing the foregoing combination. Administration of the foregoing combination to patients reduces or eliminates the incidence of hot flushes, vasomotor symptoms, night sweats, and sleep disturbance. Moreover, the risk of acquiring breast cancer and / or endometrial cancer is believed to be reduced for patients receiving this com...

AI Technical Summary

Benefits of technology

[0198]The most widely recognized fact concerning menopause is that there is a progressive decrease and finally an arrest of estrogen secretion by the ovaries. The cessation of ovarian estrogen secretion is illustrated by the marked decline in circulating 17β-estradiol (E2) levels. This easily measurable change in circulating E2 levels coupled with the beneficial effects of estrogens on menopausal symptoms and bone resorption has concentrated most of the efforts of hormone replacement therapy on various forms of estrogens as well as to combinations of estrogen and progestin in order to avoid the potentially harmful stimulatory effects of estrogens used alone on the endometrium which can result in endometrial hyperplasia and cancer.

[0199]The rapid fall in circulating 17β-estradiol (E2) at menopause, coupled with the beneficial effects of exogenous estrogens on menopausal symptoms and bone resorption has focused most of the efforts of hormone replacement therapy on various forms of estrogens as well as to combinations of estrogen and progestin in order to avoid the risk of endometrial cancer induced by estrogens administered alone.

[0200]Hormone replacement therapy (HRT), estrogen and progestin, is used in postmenopausal women for the acute symptoms arising from estrogen deficiency, particularly hot flushes and night sweats, and for the long term prevention of osteoporosis and possibly cardiovascular disease. While progestins are effective at protecting the uterus from the stimulatory effects of long term estrogen exposure, it carries its own side effects, in particular dysfunctional uterine bleeding (Archer et al., 1999). This is a frequent side effect and a common reason for women to prematurely stop hormone replacement therapy within the first 6-12 months. The classical HRT has recently been seriously questioned or even abandoned by many women following data indicating that the combination of Premarin and Provera (Prempro) causes a 26% increase in the incidence of breast cancer at 5.2 years of follow-up with a potential negative impact on cardiovascular events (Women's Health Initiative, 2002).

[0201]We feel that the increased understanding of androgen and estrogen formation and action in peripheral target tissues called intracrinology (Labrie, 1991; Labrie et al., 1992a; Labrie et al., 1992b; Labrie et al., 1994; Labrie et al., 1995; Luu-The et al., 1995a; Labrie et al., 1996; Labrie et al., 1997a; Labrie et al., 1997b; Labrie et al., 1997c; Labrie et al., 1997d) as well as our recent observations indicating the predominant role of androgens over that of estrogens in the prevention of bone loss after ovariectomy in the rat (Martel et al., 1998) and the observation of a similar situation in post-menopausal women (Labrie et al., 1997c) have paved the way for a timely and potentially highly significant progress in the field of sex steroid replacement therapy and aging. Such a possibility is well supported by our observations.

[0202]In Berger et al. (2005) it is shown particularly interesting effects of DHEA on the three layers of the vaginal wall of rat vagina, namely a highly mucified epithelium, an increased muscularis thickness and increased collagen fiber compactness in the lamina propria. Thus DHEA exerts both androgenic and estrogenic effects on the vaginal mucosa, providing a more physiological replacement therapy.

[0203]The present invention is thus based upon the recent progress achieved in our understanding of sex steroid physiology in men and women (Labrie, 1991; Labrie et al., 1992a; Labrie et al., 1992b; Labrie et al., 1994; Labrie et al., 1995a; Luu-The et al., 1995a; Labrie et al., 1997a; Labrie et al., 1997b; Labrie et al., 1997c; Labrie et al., 1997d) and the recognition that women, at menopause, are not only deprived from estrogens activity due to a declining ovarian activity, but have already been submitted for a few years to a decreasing exposure to androgens. In fact, normal women produce an amount of androgens equivalent to two thirds of the androgens secreted in men (Labrie et al., 1997a).

Problems solved by technology

Treatment of females with androgenic compounds may have the undesirable side effect of causing certain masculinising side effects.

Also, administering sex steroids to patients may increase the patient's risk of acquiring certain diseases.

In fact, estrogen replacement therapy may result in severe breast pain which may lead to discontinuation of therapy.

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