Therapy of estrogen-associated disorders

Details Therapy of estrogen-associated disorders Therapy of estrogen-associated disorders

2000-12-05

2003-07-29

Tate, Christopher R. (Department: 1651)

Drug, bio-affecting and body treating compositions

Plant material or plant extract of undetermined constitution...

C424S757000

Reexamination Certificate

active

06599536

ABSTRACT:

This is a National Stage application under 35 U.S.C. §371 of PCT Application No. AU99/00222, filed Mar. 26, 1999, corresponding to Australian Patent Application No. PP 2607, filed Mar. 26, 1998.
This invention relates to methods and compositions for the treatment, prophylaxis, amelioration or prevention of disorders associated with abnormally high activity of steroidal estrogens, using a plant extract enriched for estrogenic isoflavones preferably comprising predominantly biochanin or a high ratio of biochanin to a mixture of other estrogenic isoflavones comprising formononetin, daidzein and genistein. The targeted conditions specifically include uterine fibroids, polycystic ovarian disease, ovarian cysts, mastalgia, cyclical acne, endometriosis and endometrial hyperplasia.
The aforementioned conditions usually are considered as a group because of a number of common characteristics. They occur almost exclusively in pre-menopausal women and therefore are thought to be associated with high blood levels of steroidal sex hormones, and they are associated with benign, hyperplastic and proliferative changes in the tissues of the is female reproductive tract (with the exception of cyclical acne).
The prominent role of steroidal estrogen in thee conditions is suggested by the observations firstly that these conditions and symptoms occur almost predominantly in pre-menopausal women and usually disappear with the onset of menopause, secondly, they often get worse during the mid-phase of the menstrual cycle when cyclical estrogen levels are highest, they usually are exacerbated by the use of steroidal estrogen therapy, and lastly they usually respond to therapies such as GnrH agonists, oral contraception, or oophorectomy, all of which have the effect of reducing steroidal estrogen production in the body.
Uterine fibroids are a particularly common problem with more than 30% of women developing fibroids by the time they reach menopause. Fibroids are benign adenomas originating in the uterine wall and composed of fibrous tissue. For some women, the fibroids can be small and essentially asymptomatic. For other women, the fibroids can be of such a size to cause symptoms such as severe menstrual bleeding and uterine cramping (with fibroids that disrupt the endometrium) or constipation and urinary frequency (with large, space-occupying fibroids that grow out into the pelvic cavity). Estrogen therapy is known to aggravate fibroids and the symptoms associated with fibroids [Grodstein et al. “Postmenopausal hormone use and colecystectomy in a large prospective study.”
Obstetrics and Gynaecology
: 1994: 83(1), 5-11; Akkad et al. “Abnormal uterine bleeding on HRT: The importance of intrauterine structural abnormalities.”
Obstetrics and Gynaecology
, 1995. 86(3): 330-334; Sener et al. “The effects of HRT on uterine fibroids in postmenopausal women.”
Fertility and Sterility
, 1996. 65(2): 354-3571]. The usual treatment for fibroids is surgical removal (hysterectomy or hysterotomy).
Endometrial hyperplasia is thought to affect between 5-15% of pre-menopausal women. It involves an abnormal thickening of the endometrium that is not completely shed at the time of menstruation. The symptoms can include painful and heavy menstruation, and painful sexual intercourse. Treatment usually consists of surgery (curettage or hysterectomy).
Endometriosis affects about 5% of pre-menopausal women. This condition is due to the appearance of endometrium in the peritoneal cavity. Patches of endometrium can grow on the serosal surface of the ovaries, uterus, bladder, large intestine or the peritoneum. These patches respond to normal hormonal changes over the menstrual cycle in parallel to that of the endometrium the uterus and can bleed, swell and cause severe pelvic discomfort and pain. Standard therapy of endometriosis is surgical ablation of the abnormal tissue, although the recurrence rate is high, requiring ongoing surgical treatment [Namnoum et al. “Incidence of symptom recurrence after hysterectomy for endometriosis.”
Fertility and Sterility
, 1995. 64(5): 898-902]. Endometriosis also is aggravated by estrogen therapy [Goh et al. “Postmenopausal endometrioma and HRT”
Australia New Zealand of Obstetrics and Gynaecology
, 1992. 32(4): 384-385].
Ovarian cysts are thought to affect up to about 20% of pre-menopausal women. The pathology is that of multiple, incomplete follicles within the body of the ovary. A variant of this condition is known as polycystic ovarian disease which is characterised by excessive androgen production from the follicles stimulated by abnormally high insulin levels. Excess androgens are often converted to steroidal estrogen. The usual symptoms of polycystic ovarian disease are hirsutism and acne. The normal treatment for these conditions are GnrH agonists that function by down-regulating the release of gonadotrophins (FSH and LH) from the hypothalamus, thereby inhibiting and further ovulation.
Mastalgia is also known as cyclical mastalgia or fibrocystic breast disease. It is characterised by the retention of fluid in cysts within the fibrous tissue of the breast. It normally is associated with swelling, pain and tenderness, with symptoms usually worsening about the middle of the menstrual cycle when estradiol levels peak in the blood. No effective therapy for this condition is known.
Cyclical acne normally is restricted to post-adolescent women. It is associated with severe acne over the face and upper torso and normally the acne worsens on a cyclical basis in parallel with the menstrual cycle. The normal therapy for this condition is oral contraception in order to regulate ovulation and estrogen production.
In general, the management of these aforementioned conditions is unsatisfactory. Surgery is the most common method of treatment, and apart from the dramatic and intrusive nature of this approach, an inevitable outcome often is sterility as a result of removal of ovaries and/or uterus. The use of GnrH agonists also is not without adverse consequences as it invariably leads to premature menopause, with its attendant increased risks of osteoporosis and heart disease.
The underlying causes of or risk factors for the aforementioned conditions are unknown. Genetic risk factors are not reported, neither are lifestyle risk factors. There is no reliable epidemiological data reported that links the incidence of any one of these conditions or the group of conditions as a whole to specific communities or racial groups, or to lifestyle factors such as diet. However, it generally is recognised that the conditions or symptoms are associated with excess estrogen stimulation of tissues of the female reproductive tract and that it would be prudent to avoid any situation likely to aggravate estrogenic activity.
Plant estrogens including estrogenic isoflavones recently have come to medical attention because they mimic the effect/activity of steroidal estrogens and their biologically active analogues by binding to and activating estrogen receptors on animals (including human) cells. Plant isoflavones such as formononetin, biochanin, daidzein and genistein are known to be estrogenic in vitro, acting as agonists for the human estrogen receptor. Their ability to function as estrogens in the body is well understood and the epidemiological link between diets high in these estrogenic isoflavones and low incidences of certain estrogeneficiency states also is well documented. This has led to considerable interest in the use of dietary estrogens such as isoflavones to provide a supplementary estrogenic activity in menopausal women, providing relief from estrogen-deficiency symptoms including hot flushes, mood swings, osteoporosis, hypertension, and hypercholesterolaemia.
Given the current understanding about the estrogenic action of isoflavones, and the adverse consequences of estrogen therapy on the aforementioned pre-menopausal conditions and symptoms, estrogenic isoflavones would appear to be contra-indicated for subjects suffering from those conditions or symptoms. While the incid

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