AU2001261684A1 - Methods of treating androgen deficiency in men using selective antiestrogens - Google Patents
Methods of treating androgen deficiency in men using selective antiestrogensInfo
- Publication number
- AU2001261684A1 AU2001261684A1 AU2001261684A AU2001261684A AU2001261684A1 AU 2001261684 A1 AU2001261684 A1 AU 2001261684A1 AU 2001261684 A AU2001261684 A AU 2001261684A AU 2001261684 A AU2001261684 A AU 2001261684A AU 2001261684 A1 AU2001261684 A1 AU 2001261684A1
- Authority
- AU
- Australia
- Prior art keywords
- men
- antiestrogens
- disorder
- reduction
- antiestrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
METHODS OF TREATING ANDROGEN DEFICIENCY IN MEN USING SELECTIVE
ANTIESTROGENS
BACKGROUND OF THE INVENTION
The invention relates to the new use of antiestrogens for the production of a pharmaceutical agent for treating a relative androgen deficiency in men.
In men, increasing age leads to a reduction of testicular androgen production and androgen concentration in the organism. In contrast to the situation in women, in whom estrogen production drops to castration values within a comparatively short period, this takes decades in men and involves a gradual drop. The total concentration of testosterone in the serum in the older age group is significantly reduced compared to the values in young men. Because of the increase in steroid hormone-binding globulin (SHBG) that coincides with the aging process, moreover, the proportion of free, unbound, and thus biologically active testosterone drops. In addition, the serum levels of estrogens, although they are produced from androgens by direct conversion, do not drop in the same way as a function of age. As a result, the hormonal environment is significantly altered.
In men, the hormonal environment of the sexual steroids is characterized by a significant preponderance of
androgens over estrogens. While the circulating main component of androgens, testosterone, is detected in the serum in units in the range of nmol/1, the estrogen antagonist, estradiol, can be measured only in the range of pmol/1. This considerable preponderance of androgen can be detected basically in the entire late puberty period of life, but there is a clearly different intensity of this androgen dominance as a function of age. With increasing age and particularly so in those over the age of 60, there is a less pronounced emphasis of the androgen preponderance .
In older men there are relative decreases in the preponderance of testosterone by 30-50% compared to the previous values found in young men.
The relative testosterone deficiency per se can be regarded as responsible for a number of age-related disorders. Reduction of muscle mass accompanied by limitation of body performance capacity, reduction of bone density and in individual cases even osteoporosis, an increase in prostate size referred to as benign prostatic hyperplasia, reduction of libido and potency, and psycho-vegetative disorders such as depression, which are disorders that are often generically referred to as Male Menopause and are caused by relative androgen deficiency in men. Libido is the desire to obtain an erection, while potency is the ability to have that erection.
It is known that in younger men, testosterone values are also effectively increased by daily treatment with
antiestrogens to treat male infertility. Treatment of Male Infertility, Springer-Verlag Berlin, Heidelberg, New York 1982; Fuse, H. et al . , Archives of Andrology 31 (1993) 139- 145); Nonsurgical Treatment of Male Infertility, Jarow, J., Infertility in the Male, pp. 410-422. However, it has been thought that antiestrogens do not seem well suited for treatment of a relative androgen deficiency in men. Thus, for example, U.S. patent 5,861,389 proposes the use of at least one aromatase inhibitor for the production of a pharmaceutical agent for treating a relative androgen deficiency in men.
SUMMARY OF THE INVENTION
The object of the present invention is to treat a relative androgen deficiency in older men and/or the specific disorders related to male menopause by the use of antiestrogens .
It has been noted that the use of antiestrogens in treating a relative androgen deficiency in older men results surprisingly in a long-term increase in the androgen level.
By gradually stimulating the body to produce testosterone, the antiestrogens result in an endogenic rebalancing of the testosterone/estrogen ratio in men. As a result, the relative androgen deficiency is compensated for.
For the purposes of this invention, antiestrogens are all those compounds that compete with estrogen for estrogen-receptor-binding sites and may delay replenishment of
intracellular estrogen receptors. As antiestrogens, therefore, all such compounds are suitable, such as, for example : tamoxifen citrate which is the trans-isomer of a triphenylethylene derivative. The chemical name is (Z)2-[4-
(1,2-diphenyl-l-butenyl) phenoxy] -N, N-dimethylethanamine 2- hydroxy-1, 2, 3- propanetricarboxylate (1:1) and sold under the trademark Novladex; and clomiphene citrate which is 2[p-(2- chloro-1,2- diphenylvinyl) phenoxy]] trieth la ine citrate (1:1). It has the molecular formula of C26H28C1N0»C6H807 and a molecular weight of 598.09 and is sold under the trademark Clomid.
The list of antiestrogens above is not exhaustive, other compounds that meet the set requirements, are also considered.
A pharmaceutically effective dosage of the antiestrogen is administered in older men for an effective time period, preferably continuously. For example, at a daily dose of 5-10 mg once or twice a day, tamoxifen is administered to obtain a target range of mid-normal testosterone levels. A dose of 10-25 mg of clomid daily or every other day and up to 100 mg is administered to obtain the mid-normal levels. Measuring the serum concentration of testosterone and estradiol can thus give early indication of whether the desired hormone balance was achieved and optionally whether dose adjustment can be undertaken.
In general, 5 to 1000 mg, preferably 10 to 100 mg, of antiestrogen clomiphene citrate or tamoxifen citrate or a biologically equieffective amount of another antiestrogen is used daily or every other day to treat a relative androgen deficiency in men.
The antiestrogens can be administered, e.g., orally, parenterally or transdermally by a patch for example.
For the preferred oral administration, suitable means are especially tablets, coated tablets, capsules, pills, suspensions, or solutions that can be produced in a way that is commonly used and familiar to one skilled in the art, with the additives and vehicles that are commonly used for the formulation of antiestrogens that are to be administered orally.
The pharmaceutical agent that is produced according to the invention contains as an active ingredient per dosage unit of the antiestrogen at a daily or every other day dosage of 5 to 100 mg in addition to the commonly used additives, vehicles and/or diluents or other antiestrogens at biologically equieffective dosages.
When antiestrogens are used for treating male menopause, the estrogen concentration is effectively lowered. The easy controllability of the treatment distinguishes treatment with an antiestrogen. For 10 mg tablets, each tablet contains 15.2 mg of tamoxifen citrate which is equivalent to 10 mg of tamoxifen. For 20 mg tablets, each
tablet contains 30.4 mg of tamoxifen citrate which is equivalent to 20 mg of tamoxifen. The inactive ingredients are carboxy ethylcellulose calcium, magnesium stearate, mannitol and starch.
Clomiphene citrate tablets is a mixture of two geometric isomers [cis (zuclomiphene) and trans (enclomiphene) ] containing between 30% and 50% of the cis- isomer. A standard commercially available tablet contains 50 mg clomiphene citrate and the following inactive ingredients: corn starch, lactose, magnesium stearate, pregelatinized corn starch, and sucrose. The current tablets are used primarily for treating female infertility. Treatment according to the present invention contemplates a redosing to accommodate the lower dosages specified herein.
It is also contemplated that combinations of antiestrogens can be administered or that combinations of antiestrogens and other testosterone producing drugs can be used.
Claims (12)
1. A method of treating androgen deficiency in men comprising administering a selective antiestrogen.
2. The method according to claim 1, wherein the selective antiestrogen is clomiphene.
3. The method according to claim 1, wherein the selective antiestrogen is clomiphene citrate.
4. A method of treating disorders related to male menopause in men comprising administering an antiestrogen.
5. The method according to claim 4, wherein the disorder is reduction of muscle mass.
6. The method according to claim 4, wherein the disorder is limitation of body performance capacity.
7. The method according to claim 4, wherein the disorder is reduction of bone density.
8. The method according to claim 4, wherein the disorder is reduction of libido.
9. The method according to claim 4, wherein the disorder is reduction of potency.
10. The method according to claim 4, wherein the disorder is reduction of benign prostatic hyperplasia.
11. The method according to claim 1, wherein the selective antiestrogen is tamoxifen.
12. The method according to claim 1, wherein the selective antiestrogen is tamoxifen citrate.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US20749600P | 2000-05-26 | 2000-05-26 | |
US60/207,496 | 2000-05-26 | ||
PCT/US2001/015900 WO2001091744A1 (en) | 2000-05-26 | 2001-05-15 | Methods of treating androgen deficiency in men using selective antiestrogens |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2001261684A1 true AU2001261684A1 (en) | 2002-02-28 |
AU2001261684B2 AU2001261684B2 (en) | 2006-01-12 |
Family
ID=22770819
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU2001261684A Ceased AU2001261684B2 (en) | 2000-05-26 | 2001-05-15 | Methods of treating androgen deficiency in men using selective antiestrogens |
AU6168401A Pending AU6168401A (en) | 2000-05-26 | 2001-05-15 | Methods of treating androgen deficiency in men using selective antiestrogens |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU6168401A Pending AU6168401A (en) | 2000-05-26 | 2001-05-15 | Methods of treating androgen deficiency in men using selective antiestrogens |
Country Status (7)
Country | Link |
---|---|
US (1) | US6391920B1 (en) |
EP (1) | EP1289519B1 (en) |
JP (1) | JP2003534375A (en) |
AU (2) | AU2001261684B2 (en) |
BR (1) | BR0111141A (en) |
CA (1) | CA2409647C (en) |
WO (1) | WO2001091744A1 (en) |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7067557B2 (en) * | 2000-05-26 | 2006-06-27 | Harry Fisch | Methods of treating androgen deficiency in men using selective antiestrogens |
RU2297218C2 (en) * | 2001-07-09 | 2007-04-20 | Зонаджен, Инк. | Methods and materials for treating testosterone failure in men |
US7737185B2 (en) | 2001-07-09 | 2010-06-15 | Repros Therapeutics Inc. | Methods and compositions with trans-clomiphene |
US7173064B2 (en) * | 2001-07-09 | 2007-02-06 | Repros Therapeutics Inc. | Methods and compositions with trans-clomiphene for treating wasting and lipodystrophy |
US20040214898A1 (en) * | 2001-11-29 | 2004-10-28 | Steiner Mitchell S. | Methods for treating hot flashes |
US20060269611A1 (en) * | 2001-11-29 | 2006-11-30 | Steiner Mitchell S | Prevention and treatment of androgen-deprivation induced osteoporosis |
US20070197664A1 (en) * | 2001-11-29 | 2007-08-23 | Steiner Mitchell S | Prevention and treatment of androgen-deprivation induced osteoporosis |
US20080249183A1 (en) * | 2001-11-29 | 2008-10-09 | Steiner Mitchell S | Treatment of androgen-deprivation induced osteoporosis |
US20050080143A1 (en) * | 2001-11-29 | 2005-04-14 | Steiner Mitchell S. | Treatment of androgen-deprivation induced osteoporosis |
US7524866B2 (en) | 2001-11-29 | 2009-04-28 | Gtx, Inc. | Prevention and treatment of androgen—deprivation induced osteoporosis |
MX2007000050A (en) * | 2004-07-14 | 2007-07-10 | Repros Therapeutics Inc | Trans-clomiphene for the treatment of benign prostate hypertrophy, prostate cancer, hypogonadism, elevated triglycerides and high cholesterol. |
CA2578852A1 (en) * | 2004-09-03 | 2006-03-09 | Hormos Medical Corporation | Use of a selective estrogen receptor modulator for the manufacture of a pharmaceutical preparation for use in a method for the treatment or prevention of androgen deficiency |
BRPI0606528A8 (en) * | 2005-02-04 | 2018-03-13 | Repros Therapeutics Inc | composition for use in the manufacture of male infertility treatment medicines |
JP5785680B2 (en) * | 2005-03-22 | 2015-09-30 | リプロス セラピューティクス インコーポレイテッド | Dosing regimen for trans-clomiphene |
US20110118355A1 (en) * | 2007-09-21 | 2011-05-19 | Harry Fisch | Treatment of migraine headaches using antiestrogens |
WO2009039344A1 (en) * | 2007-09-21 | 2009-03-26 | Harry Fisch | Treatment of migraine headaches using antiestrogens |
CA2702710C (en) | 2007-10-16 | 2013-05-07 | Repros Therapeutics, Inc. | Trans-clomiphene for metabolic syndrome |
US20090215733A1 (en) * | 2008-02-26 | 2009-08-27 | Michael Charles Scally | Therapy for the prophylaxis or treatment of adverse body composition changes and/or decreased muscle strength after androgen or gnrh analogue intake |
UA113291C2 (en) | 2011-08-04 | 2017-01-10 | TRANSCLOMYPHENE METABOLITES AND THEIR APPLICATIONS | |
CA2881604C (en) * | 2011-08-09 | 2021-09-14 | Kenneth W. Adams | Use of aromatase inhibitor or estrogen blocker for increasing spermatogenesis or testosterone levels in males |
ES2681023T3 (en) * | 2012-02-29 | 2018-09-11 | Repros Therapeutics Inc. | Combination therapy to treat androgen deficit |
CN104994877A (en) | 2012-11-02 | 2015-10-21 | 利普生物药剂公司 | Trans-clomiphene for use in cancer therapy |
US9744177B2 (en) * | 2014-03-10 | 2017-08-29 | Endorecherche, Inc. | Treatment of male androgen deficiency symptoms or diseases with sex steroid precursor combined with SERM |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4729999A (en) * | 1984-10-12 | 1988-03-08 | Bcm Technologies | Antiestrogen therapy for symptoms of estrogen deficiency |
DE3660489D1 (en) * | 1985-06-08 | 1988-09-15 | Asta Pharma Ag | Derivatives of 1,1,2,2-tetramethyl-1,2-bis(2-fluoro-4-hydroxyphenyl) ethane |
US4820736A (en) * | 1987-03-20 | 1989-04-11 | Yale University | Use of clomiphene to predict fertility in a human female |
US5776923A (en) | 1993-01-19 | 1998-07-07 | Endorecherche, Inc. | Method of treating or preventing osteoporosis by adminstering dehydropiandrosterone |
DE4435368A1 (en) | 1994-09-22 | 1996-03-28 | Schering Ag | Use of aromatase inhibitors for the manufacture of a medicament for the treatment of a relative androgen deficiency in men |
US5952319A (en) * | 1997-11-26 | 1999-09-14 | Research Triangle Institute | Androgenic steroid compounds and a method of making and using the same |
DE19825591A1 (en) * | 1998-06-09 | 1999-12-23 | Jenapharm Gmbh | Pharmaceutical combinations to compensate for a testosterone deficit in men while protecting the prostate |
US20060269611A1 (en) * | 2001-11-29 | 2006-11-30 | Steiner Mitchell S | Prevention and treatment of androgen-deprivation induced osteoporosis |
-
2001
- 2001-05-15 JP JP2001587759A patent/JP2003534375A/en active Pending
- 2001-05-15 US US09/980,652 patent/US6391920B1/en not_active Expired - Lifetime
- 2001-05-15 AU AU2001261684A patent/AU2001261684B2/en not_active Ceased
- 2001-05-15 BR BR0111141-8A patent/BR0111141A/en not_active Application Discontinuation
- 2001-05-15 EP EP01935605.4A patent/EP1289519B1/en not_active Expired - Lifetime
- 2001-05-15 CA CA2409647A patent/CA2409647C/en not_active Expired - Lifetime
- 2001-05-15 AU AU6168401A patent/AU6168401A/en active Pending
- 2001-05-15 WO PCT/US2001/015900 patent/WO2001091744A1/en active IP Right Grant
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