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WO1998006404A1 - Combinaisons pour hormonotherapie substitutive contenant un oestrogene, un progestatif et un androgene naturels - Google Patents

Combinaisons pour hormonotherapie substitutive contenant un oestrogene, un progestatif et un androgene naturels Download PDF

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Publication number
WO1998006404A1
WO1998006404A1 PCT/GB1997/002133 GB9702133W WO9806404A1 WO 1998006404 A1 WO1998006404 A1 WO 1998006404A1 GB 9702133 W GB9702133 W GB 9702133W WO 9806404 A1 WO9806404 A1 WO 9806404A1
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Prior art keywords
natural
use according
liter
level
oestrogen
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.)
Ceased
Application number
PCT/GB1997/002133
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English (en)
Inventor
Adam Henry Carey
Beverly Jane Carey
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REPRODUCTIVE MEDICINE TRUST
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REPRODUCTIVE MEDICINE TRUST
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Application filed by REPRODUCTIVE MEDICINE TRUST filed Critical REPRODUCTIVE MEDICINE TRUST
Priority to AU37808/97A priority Critical patent/AU3780897A/en
Publication of WO1998006404A1 publication Critical patent/WO1998006404A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone

Definitions

  • the present invention relates to the use of a combination of hormones in the treatment of menopausal or post-menopausal disorders in women.
  • Oestrogen replacement therapy although beneficial in many ways, has one serious side effect with important implications: oestrogen tends to cause stimulation of the endometrium. Before the menopause, this tendency is opposed by another hormone of the ovarian endocrine cycle, namely progesterone. The interaction between the effects of these two hormones leads to the endometrium being repeatedly stimulated and then shed in a monthly cycle with no net thickening. If prolonged oestrogen replacement therapy is taken in the absence of progesterone or a substance with progesterone-like activity, known as a progestogen, the oestrogen will cause unopposed stimulation of the endometrium which may eventually develop into cancer.
  • progesterone a substance with progesterone-like activity
  • Progestogens may be natural or synthetic.
  • the natural progestogens include progesterone and pregnenolone which are not orally active, and therefore are not offered in conventional medical practice as progestogenic oppositions for oestrogen replacement therapy.
  • progesterone There are only two products listed in the British National Formulary under "progesterone". These are a pessary for administration per vaginu or per rectum (Cyclogest®, Hoechst) and an intramuscular injection (Gestone®, Ferring) . The two products are indicated for prevention of recurrent miscarriage, progesterone being a pro-gestational hormone.
  • progesterone analogues dehydrogesterone, hydroxyprogesterone and medroxyprogesterone
  • testosterone analogues norethisterone and norgestrel and their derivatives are examples of progesterone analogues.
  • Synthetic progestogens are described as anectodally as "a necessary evil". They are taken to prevent endometrial cancer, but the concern is that they may act to antagonise the beneficial effects of oestrogen replacement therapy, for example by altering serum lipids to increase the risk of cardiovascular disease. Furthermore, they often produce unacceptable side effects such as abdominal bloating, breast tenderness, headaches, hair loss, emotional lability or breakthrough bleeding. Different progestogens have different side effect profiles, but it is not uncommon that an individual woman cannot find an acceptable progestogen and chooses to undergo major surgery in the form of a hysterectomy so that she can continue to take oestrogen replacement therapy without the need for progestogenic opposition.
  • Oestrogens and progestogens may be taken as tablets. For women with a uterus, the oestrogen tablet is taken every day with the addition of a tablet of progestogen for seven to ten days each month to provoke a menstrual bleed.
  • Patches usually contain oestrogen alone but may also contain progestogen. They are applied to the buttock or arm and changed once or twice a week.
  • the advantage over tablets is that the hormone is absorbed transder ally, therefore avoiding the so-called "first pass effect" of hormones passing through the liver on the way from the gut to the systemic circulation and thereby activating liver enzymes and altering blood lipids.
  • the disadvantage of patches is that they are unsightly, often cause a local irritation at the site of application and tend to fall off in hot weather.
  • Implants are tiny pellets of oestradiol or testosterone which are inserted by a doctor, every six months, under the skin of the anterior abdominal wall or the buttock. Their advantage is the improved compliance; their disadvantage that if the treatment is unacceptable it can be very difficult to remove the implant. Further some women develop reduced sensitivity to the extremely high serum levels of oestradiol achieved. This results in the onset of menopausal symptoms as serum levels fall despite serum levels of oestradiol which are within the therapeutic range.
  • Oestradiol is produced in gel form (Oestrogel®, Hoechst; Sandrena®, Orgaron) .
  • a metered dose is applied daily to the upper arms or thighs and rubbed in. It presents all the advantages of avoiding the first pass effect whilst not needing to wear an unsightly patch or undergo a minor surgical procedure every six months.
  • progesterone is not currently indicated for use in combination with oestrogen for hormone replacement therapy.
  • Magos A.L. and Studd J.W.W. in Progress in Obstetrics and Gynaecology. Vol. 8, pages 313-334 (J.W.W. Studd Ed.) found that a combination of progesterone with oestradiol resulted in irregular breakthrough bleeding.
  • progesterone in doses high enough to preventf ⁇ ndometrial hyperplasia is associated with unacceptable drowsiness due to the action of progesterone as a central nervous system depressant.
  • progesterone is often confused with the synthetic progestogens. Important differences in their chemical structure which could lead to different actions and side effect profiles have not been considered.
  • Dr. J.R. Lee is a physician in the United States who has lectured widely and written two books (Natural Progesterone, the Multiple Roles of a Remarkable Hormone and What your Doctor may not tell you about Menopause - the Breakthrough Book on Natural Progesterone) .
  • These books allege a wide variety of beneficial effects of natural progesterone, but also contest the beneficial effects of oestrogen. They discount the evidence which supports the use of oestrogen, and they do not propose a combination therapy. Indeed, they suggest that oestrogen is used to excess and is thus responsible for most gynaecological complaints.
  • the androgens which include testosterone, androstenedione and dehydroepiandrosterone, are considered to be male hormones, although they are also produced by the ovaries.
  • Testosterone is not commonly offered in preparation of hormone replacement therapy for women. There is a concern that supplementation of women with this male hormone may have an adverse effect on their risk of cardiovascular disease. Testosterone is also not indicated for women because of the possibility of masculinising side effects, such as facial hair and acne.
  • J.W.W. Studd, W.P. Collins and J.R. Newton in Journal of Obstetrics and Gynaecology. Vol.84, pages 314-315 (1977) have suggested that testosterone may have a valuable role for some women in improving libido after the menopause.
  • a hormone replacement therapy comprising a combination of natural oestrogens, progestogens and androgens provides beneficial synergistic effects.
  • the present invention provides the use of a natural oestrogen, a natural progestogen and a natural androgen as a combined preparation for simultaneous, separate or seguential use in the treatment of menopausal or post-menopausal disorders in women.
  • the natural oestrogen is selected from the group consisting of oestradiol, oestrone, oestriol and mixtures thereof.
  • the natural progestogen is selected from the group consisting of progesterone, pregnenolone and mixtures thereof.
  • the natural androgen is selected from the group consisting of testosterone, androstenedione, dehydroepiandrosterone (DHEA) and mixtures thereof. More preferably, the natural oestrogen consists essentially of oestradiol, the natural progestogen consists essentially of progesterone, and the natural androgen consists essentially of testosterone.
  • the combined preparation used in the present invention preferably has the natural oestrogen, natural progestogen and natural androgen in admixture with a suitable pharmaceutical excipient for simultaneous administration of all three hormones.
  • the combined preparation can be adapted for oral, transdermal (patch, cream or gel) , subcutaneous implant, vaginal, rectal or parenteral administration. Preferred formats are those already used for HRT and oral contraceptive hormone administration.
  • the combined preparation may, of course, comprise different hormones in different formats for separate or sequential use.
  • the combined preparation could comprise the oestrogen and androgen in oral adminstration format, and the progestogen in a* transdermal administration format.
  • the hormones may, of course, be in the form of biologically acceptable prodrugs such as esters for sustained release in vivo.
  • the hormone concentrations and excipients used in the various combined preparation formats will be similar to those used for the administration of contraceptive hormones to pre-menopausal women, and/or the existing HRT therapies described above.
  • the dosage levels will depend on the bioavailability of the hormones in each given format. For example, there is a well known "first pass" effect with oral administration of these hormones, whereby a substantial fraction of the hormone is initially removed by the liver. Therefore, it is only really practicable to define the present invention in terms of the salivary and serum levels of the hormones that are to be achieved for the duration of the therapy.
  • the use according to the present invention achieves a salivary oestradiol level of 0.5 - 500 pg/ml, more preferably 5 - 300 pg/ml, and most preferably 50 - 300 pg/ml, or a serum oestradiol level of 100 - 1650 pmol/liter, more preferably 250 - 1,650 pmol/liter.
  • the use according to the present invention achieves a serum oestrone level of from 5 - 50 ⁇ mol/liter, more preferably 10 - 50 ⁇ mol/liter, or a salivary oestrone level of 30 to 90 pmol/liter.
  • the use according to the present invention achieves a serum oestriol level of from 1 - 1,000 ⁇ mol/liter, preferably 10 - 1,000 ⁇ mol/liter and most preferably 100 - 800 ⁇ mol/liter, or a salivary oestriol level of from 1 to 10 nmol/liter.
  • the use according to the present invention achieves a serum testosterone level of from 0.1 to 30 nmol/liter or a salivary testosterone level of from 18 - 140 pg/ml, more preferably 30 - 140 pg/ml, and most preferably 50 - 80 pg/ml.
  • the use according to the present invention achieves a salivary dehydroepiandrosterone (DHEA) level of from 40 - 300 pg/ml, more preferably 100 - 300 pg/ml.
  • the serum DHEA sulfate level is preferably 1 - 120 ⁇ mol/liter, more preferably 5 - 100 ⁇ mol/liter.
  • the use according to the present invention achieves a serum level of androstenedione in the range of 4 - 100 nmol/liter, preferably 5 -50 nmol/liter.
  • the salivary hormone levels defined above are determined using kits from Aeron Life Cycles Laboratories, California.
  • the kits are FDA approved radioimmunoassay kits.
  • radioimmunoassay or enzyme-linked immunosorbent assay (ELISA) methods may be applied, with minor modification, to the determinations of these hormones in serum.
  • Suitable antibodies for use in the assays are available commercially, for example from Diagnostic Products Corp. (U.K.) and Scheron Diagnostics (U.K.).
  • menopausal or post-menopausal disorders that can be treated in accordance with the present invention include: osteopenia and osteoporosis; hypercholesterolaemia, hypertension and atherosclerotic arterial disease; vasomotor instability including hot flushes and night sweats; urogenital atrophy including detrusor instability and stress incontinence; poor libido; skin, hair and nail problems; anxiety, depression and insomnia; memory loss and pre-senile dementia, and mixtures thereof.
  • the combined preparations used in the present invention can also be used for the treatment of certain other hormone related deficiency conditions, including women with premature ovarian failure, Turner's syndrome, testicular feminisation syndrome, sex change, hermaphroditism and pseudohermaphroditism, premenstrual syndrome, addback HRT for use with gonadotropin-releasing hormone analogues for endometriosis, pelvic pain, pelvic venous congestion, and benign breast disease.
  • hormone related deficiency conditions including women with premature ovarian failure, Turner's syndrome, testicular feminisation syndrome, sex change, hermaphroditism and pseudohermaphroditism, premenstrual syndrome, addback HRT for use with gonadotropin-releasing hormone analogues for endometriosis, pelvic pain, pelvic venous congestion, and benign breast disease.
  • this invention provides a method for the treatment of any of the disorders enumerated above, comprising administering to a human patient a therapeutically effective amount of a natural oestrogen, a natural progtestogen and a natural androgen as a combined preparation.
  • the oestradiol, progesterone and testosterone were administered in conventional formats, the guantities of each being titrated to achieve the following serum levels: Oestradiol 300-1000 pmol/liter; progesterone 5-50 nmol/liter; and testosterone 2-4 nmol/liter.
  • the testosterone serum levels were determined by competitive radioimmunoassay on an ATS 180 automated machine using labelled antibody supplied by Scheron Diagnostics (UK) .
  • the oestradiol and progesterone serum levels were determined by automated ELISA on a Boehringer Mannheim ES700 machine using antibody supplied by Diagnostic Products Corp. (UK) .
  • the measured between-batch coefficients of variation were: oestradiol 12.5% (at 200 pmol/liter); testosterone 10.8% (at 3.1 nmol/liter); and progesterone 9.2% (at 32 nmol/liter).
  • Synthetic progestogen was offered as either dydrogesterone lOmg or medroxyprogesterone acetate 5mg taken daily for the first ten days of each calendar month.
  • Ps synthetic progestogen (dydrogesterone, norethisterone or medroxyprogesterone acetate)

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un oestrogène naturel, d'un progestatif naturel et d'un androgène naturel sous forme d'une préparation combinée. Cette préparation peut être utilisée simultanément, séparément ou de manière séquentielle, pour traiter les troubles ménopausiques ou post-ménopausiques chez la femme. De préférence, le traitement consiste à administrer simultanément un mélange d'oestradiol, progestérone et testostérone.
PCT/GB1997/002133 1996-08-09 1997-08-08 Combinaisons pour hormonotherapie substitutive contenant un oestrogene, un progestatif et un androgene naturels Ceased WO1998006404A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37808/97A AU3780897A (en) 1996-08-09 1997-08-08 Combinations for hormone replacement therapy containing a natural oestrogen, a natural progestogen and a natural androgen

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9616700.2A GB9616700D0 (en) 1996-08-09 1996-08-09 Hormone supplement
GB9616700.2 1996-08-09

Publications (1)

Publication Number Publication Date
WO1998006404A1 true WO1998006404A1 (fr) 1998-02-19

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PCT/GB1997/002133 Ceased WO1998006404A1 (fr) 1996-08-09 1997-08-08 Combinaisons pour hormonotherapie substitutive contenant un oestrogene, un progestatif et un androgene naturels

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AU (1) AU3780897A (fr)
GB (1) GB9616700D0 (fr)
WO (1) WO1998006404A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002092102A3 (fr) * 2001-05-16 2003-03-20 Endeavor Pharmaceuticals Traitement d'etats lies a un deficit en hormones par administration de progestatifs
WO2003041741A1 (fr) * 2001-11-15 2003-05-22 Pantarhei Bioscience B.V. Methode de prevention ou de traitement de troubles gynecologiques benins
EP1623712A3 (fr) * 1998-06-11 2009-12-16 Endorecherche Inc. Combinaisons de modulateurs des récepteurs oestrogène et de déhydroépiandrostérone (DHEA) ou analogues
US7666827B2 (en) 2004-09-15 2010-02-23 The Procter & Gamble Company Wet wipe lotions comprising particulate material
EP1792629A4 (fr) * 2004-08-25 2010-08-25 Takeda Pharmaceutical Agents preventifs/remedes pour l'incontinence de stress et procede de selecetion de ceux-ci
US20110086825A1 (en) * 2009-10-13 2011-04-14 Chatroux Sylvia S Therapeutic vaginal emollient
US9125816B2 (en) 2000-08-30 2015-09-08 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism
US10285998B1 (en) 2018-04-04 2019-05-14 The Menopause Method, Inc. Composition and method to aid in hormone replacement therapy

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ALDEN J.C.: "Osteoporosis - A review", CLIN. THER., 1989, 11/1 (3-14), USA, XP002045940 *
BOUDET J. ET AL: "Study of the epicutaneous kinetic diffusion of a cream containing estrone, estradiol, testosterone and pregnenolone (Fadiamone (R)) in menopausal women", NOUV. DERMATOL., 1994, 13/9 (658-661), FRANCE, XP002045939 *
FERNANDEZ-GUASTI, ALONSO ET AL: "Synergistic action of estradiol, progesterone and testosterone on rat proceptive behavior", PHYSIOL. BEHAV., 1991, 50, 1007-11, XP002045941 *
HARGROVE J.T. ET AL: "An alternative method of hormone replacement therapy using the natural sex steroids", INFERTILITY AND REPRODUCTIVE MEDICINE CLINICS OF NORTH AMERICA, 1995, 6/4 (653-674), USA, XP002045938 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7943603B2 (en) 1998-06-11 2011-05-17 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
EP2399582A1 (fr) * 1998-06-11 2011-12-28 Endorecherche Inc. Modulateur sélectif de récepteur d'ýstrogène combiné avec déhydroépiandrostérone (DHEA) ou des analogues
EP1623712A3 (fr) * 1998-06-11 2009-12-16 Endorecherche Inc. Combinaisons de modulateurs des récepteurs oestrogène et de déhydroépiandrostérone (DHEA) ou analogues
US9132089B2 (en) 2000-08-30 2015-09-15 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism
US9125816B2 (en) 2000-08-30 2015-09-08 Besins Healthcare Inc. Pharmaceutical composition and method for treating hypogonadism
WO2002092102A3 (fr) * 2001-05-16 2003-03-20 Endeavor Pharmaceuticals Traitement d'etats lies a un deficit en hormones par administration de progestatifs
US7683047B2 (en) 2001-05-16 2010-03-23 Barr Laboratories, Inc. Treatment of conditions relating to hormone deficiencies by administration of progestins
US8076319B2 (en) 2001-05-16 2011-12-13 Barr Laboratories, Inc. Treatment of conditions relating to hormone deficiencies by administration of progestins
US7427609B2 (en) 2001-05-16 2008-09-23 Barr Laboratories, Inc. Treatment of conditions relating to hormone deficiencies by administration of progestins
WO2003041741A1 (fr) * 2001-11-15 2003-05-22 Pantarhei Bioscience B.V. Methode de prevention ou de traitement de troubles gynecologiques benins
US8071576B2 (en) 2001-11-15 2011-12-06 Pantarhei Bioscience B.V. Method of preventing or treating benign gynaecological disorders
US8685924B2 (en) 2004-08-25 2014-04-01 Takeda Pharmaceutical Company Limited Preventives/remedies for stress urinary incontinence and method of screening the same
EP1792629A4 (fr) * 2004-08-25 2010-08-25 Takeda Pharmaceutical Agents preventifs/remedes pour l'incontinence de stress et procede de selecetion de ceux-ci
EP2248524A3 (fr) * 2004-08-25 2011-03-09 Takeda Pharmaceutical Company Limited Agents preventifs/remedes pour l'incontinence de stress et procede de selecetion de ceux-ci
US7666827B2 (en) 2004-09-15 2010-02-23 The Procter & Gamble Company Wet wipe lotions comprising particulate material
US7977301B2 (en) 2004-09-15 2011-07-12 The Procter & Gamble Company Wet wipe lotions comprising particulate material
US20110086825A1 (en) * 2009-10-13 2011-04-14 Chatroux Sylvia S Therapeutic vaginal emollient
US10285998B1 (en) 2018-04-04 2019-05-14 The Menopause Method, Inc. Composition and method to aid in hormone replacement therapy

Also Published As

Publication number Publication date
AU3780897A (en) 1998-03-06
GB9616700D0 (en) 1996-09-25

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