WO2003090754A1 - Utilisation de la dhea pour le traitement de l'hypopituitarisme chez la femme - Google Patents

Utilisation de la dhea pour le traitement de l'hypopituitarisme chez la femme Download PDF

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Publication number
WO2003090754A1
WO2003090754A1 PCT/SE2003/000644 SE0300644W WO03090754A1 WO 2003090754 A1 WO2003090754 A1 WO 2003090754A1 SE 0300644 W SE0300644 W SE 0300644W WO 03090754 A1 WO03090754 A1 WO 03090754A1
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dhea
women
treatment
female
effects
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PCT/SE2003/000644
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English (en)
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WO2003090754A9 (fr
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Bengt-Åke BENGTSSON
Gudmundur Johannsson
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Sahltech I Göteborg AB
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Priority to AU2003224561A priority Critical patent/AU2003224561A1/en
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Publication of WO2003090754A9 publication Critical patent/WO2003090754A9/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A61P5/04—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH

Definitions

  • DHEA oral dehydroepiandrosterone
  • DHEA Dehydroepiandrosterone
  • T androstenedione
  • DHT Dehydroepiandrosterone
  • apo Apolipoprotein
  • CV coefficient of variation
  • DHEA dehydroepiandrosterone
  • DHEAS dehydroepiandrosterone sulfate
  • HDL high density lipoprotein
  • HL hepatic lipase
  • HSCL hepatic lipase
  • DHEA raised serum levels of DHEAS 24 h after intake to the upper normal range and increased androstenedione and T levels to the lower normal ranges.
  • ICTP carboxyl-terminal cross-linked telopeptide of type I collagen
  • LPL lipoprotein lipase
  • PICP carboxyl-terminal propeptide of type I procollagen.
  • a score for neutral body hair was calculated from the sum of the scores obtained from the forearm and leg (0-8 points), and a hormonal score was calculated from nine other skin areas (0-36 points) as described previously (11).
  • Biochemistry DHEAS was measured with a solid phase RIA (Coat-A-Count, Diagnostic Products, Los Angeles, CA), androstenedione was measured using an RIA (Ortho- Clinical Diagnostics, Amersham Pharmacia Biotech, Poole, UK), and serum total T was measured using a competitive immunoassay (Diagnostic Products).
  • the intraassay coefficients of variation (CV) and the detection limits for DHEAS, androstenedione, and T were 5% and 0.03 ⁇ mol/liter, 4% and 0.07 nmol/liter, and 7-20% and 0.10 nmol/liter, respectively.
  • Serum levels of SHBG were measured with time-resolved, noncompetitive, sandwich fluoroimmunoassays (AutoDELFIA SHBG kit, Wallac, Inc., Turku, Finland), and serum concentrations of IGF-I and insulin were measured using competitive immunoassays from Nichols Institute Diagnostics (San Juan Capistrano, CA) and Pharmacia Diagnostika (Pharmacia Insulin RIA, Uppsala, Sweden), respectively.
  • the intraassay CNs was 4.6%, 7%, and 2.5-4.2%) for SHBG, insulin, and IGF-I, respectively.
  • Serum concentrations of osteocalcin CIS Biointernational, Oris Industries, Gif-
  • ICTP carboxyl-terminal cross-linked telopeptide of type I collagen
  • PICP carboxyl-terminal propeptide of type I procollagen
  • Serum cholesterol and triglycerides were determined using fully enzymatic methods (Roche Molecular Biochemicals) with a Cobas Fara autoanalyzer (Hoffman- LaRoche Inc., Basel, Switzerland) that had within- assay CVs of 0.9% and 1.1%, respectively.
  • High density lipoprotein (HDL) cholesterol was determined after precipitation of apolipoprotein B (apoB)-containing lipoproteins with manganese chloride and heparin. The low density lipoprotein cholesterol concentration was calculated.
  • HDL high density lipoprotein
  • ApoA-1 and apoB were determined by immunoturbidometric assays (UniKit Roche, Hoffman-LaRoche Inc.). Serum lipoprotein(a) was measured by RIA (Mercodia AB, Uppsala, Sweden). The intraassay CNs of ApoA-1, apoB, and lipoprotein(a) were 2.3%, 1.9%, and 4.4%, respectively.
  • heparin 100 U/kg BW was given iv. Venous blood samples were drawn after 15 min into precooled Vacutainer tubes containing heparin. The tubes were immediately placed in ice water, and plasma was recovered by centrifugation. The samples were frozen at -80 C pending assay as described previously (12). All measurements were made in triplicate. Lipase activity is expressed as milliunits per ml plasma, where 1 mU corresponds to the release of 1 nmol fatty acid/min at 25 C and pH 8.5.
  • Fibrinogen, tissue plasminogen activator antigen, and plasminogen activator inhibitor 1 activity were measured as described previously (13). Hemoglobin concentration, hematocrit, plasma glucose, glycosylated hemoglobin, electrolytes, creatinine, liver enzymes, and free T 4 were measured using routine in-house methods.
  • Body composition and handgrip Bone mineral content and bone mineral density in total body, lumbar spine, and femoral neck; lean body mass and fat mass were determined using dual energy x-ray absorptiometry (DPX-L, Lunar Corp., Madison, WI).
  • the height from a firm bed to the umbilicus was measured in the supine position using a digital sagittalometer.
  • Handgrip strength on the dominant side was measured using an electronic grip force measurement instrument, which measures the maximum momentary force and the mean force over a set period of 10 sec in ⁇ ewtons (14). Verbal instructions were given to encourage maximum force production.
  • the results from handgrip strength were compared with normal reference values adjusted for age and sex (15), and an observed/predicted ratio was calculated for each woman.
  • the Hopkins Symptom Check List (HSCL) is composed of 56 items that cover psychiatric and somatic problems related to mental distress (16). The items can be gathered into 8 subscales: anxiety, depression, tension, cognition, inferiority, interpersonal sensitivity, somatization, and fearfulness.
  • the Psychological General Weil- Being index was also employed. This is another generic quality of life measure that assesses perceived health, anxiety, ability to cope, and depression (17).
  • Serum morning levels of DHEAS, androstenedione, and T increased markedly in the DHEA-treated group compared with placebo.
  • Serum DHEAS 12 h after dosage and at trough levels reached normal concentrations. Androstenedione and T reached subnormal reference ranges.
  • the serum androgen levels determined after 6 months of treatment were not statistically different in the women above and below 45 yr of age receiving 20 and 30 mg DHEA, respectively (DHEAS, 2.53 ⁇ 1.37 and 3.53 ⁇ 1.84 ⁇ mol/liter; androstenedione, 0.54 ⁇ 0.44 and 0.93 ⁇ 1.36; T, 0.17 ⁇ 0.13 and 0.20 ⁇ 0.20 nmol/liter, respectively).
  • Serum concentrations of IGF-I and SHBG were unchanged during the placebo- controlled period. In the group first allocated to placebo, SHBG decreased during the open extended phase when this group received treatment with DHEA, whereas the serum IGF-I concentration did not change.
  • Lean body mass was not affected by DHEA treatment during the controlled phase of the trial.
  • lean body mass increased after 12 months of treatment within the DHEA group and after 6 months of active treatment in the original placebo group.
  • Body weight, body fat mass, and central adiposity did not change significantly in response to treatment (data not shown).
  • Handgrip strength did not change during the 6 months of DHEA treatment compared with that during placebo administration.
  • both peak and mean handgrip strength over 10 sec increased within the placebo group after 6 months of open DHEA treatment. A similar tendency was noted in the DHEA group during the overall treatment period (data not shown).
  • Biochemical safety measures In response to the first 6 months of treatment, small increases in the hemoglobin concentration, hematocrit, and serum concentrations of AST, GGT, and ALP was observed within the normal range in each treatment group. No statistically significant differences between the two treatment groups were seen.
  • DHEA was used for androgen replacement therapy. Positive effects on behavior were observed, and although the dose of DHEA employed is the lowest reported, most women experienced the desired androgenic effects on hair and skin. Some anabolic effects were observed during the extended open phase of the trial, whereas only minor effects on lipid and glucose metabolism were detected. DHEA has been defined as a neurosteroid (18, 19) with neurotropic effects that include increased neuronal excitability ,_ ⁇ -aminobutyric acid type A receptor antagonistic properties, and alterations in synaptic transmission in the hippocampus (19, 20). DHEA may therefore influence cognitive processes.
  • DHEA did not have superior effect on quality of life compared with placebo, as assessed by two generic quality of life questionnaires. In contrast, the spouses reported few effects on behavior during placebo, but an overall improvement during treatment with DHEA.
  • the body hair scoring system used in this trial which did not include axillary and pubic hair, was not able to detect any clinically significant changes in hair growth.
  • the tissue response to DHEA is probably organ specific and dependent on the intracellular enzymes that convert DHEA to more active androgens and estrogens (3).
  • Previous studies suggest that the vaginal epithelium responds to DHEA as it does to estrogen, and breast tissue as it does to androgen, whereas the endometrium is not affected by DHEA (25, 32).
  • This study suggests that the hepatic effects of DHEA are mainly androgenic. This is best observed by the reduction seen in serum apoA-l,HDLcholesterol, and SHBG concentrations. These changes were small and transient with continuing treatment.
  • DHEA a pro- hormone metabolized locally to more potent sex steroids, might offer an effective and convenient mode of replacement.
  • the dose should be titrated individually to obtain normalization of morning serum levels of DHEAS and by monitoring clinical effects on hair and skin.
  • DHEA Dehydroepiandrosterone
  • DHEAS dehydroepiandrosterone sulfate

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Selon l'invention, une faible dose de déshydroépiandrostérone modifie le comportement des femmes atteintes d'hypopituitarisme et ne présentant pas de carence.
PCT/SE2003/000644 2002-04-23 2003-04-22 Utilisation de la dhea pour le traitement de l'hypopituitarisme chez la femme WO2003090754A1 (fr)

Priority Applications (1)

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AU2003224561A AU2003224561A1 (en) 2002-04-23 2003-04-22 Use of dhea for treatment of female hypopituitarism

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US37488202P 2002-04-23 2002-04-23
US60/374,882 2002-04-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112394102A (zh) * 2020-11-05 2021-02-23 上海交通大学医学院附属瑞金医院 一种检测垂体功能减退症的标志物及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5843932A (en) * 1993-01-19 1998-12-01 Endorcaherche, Inc. Therapeutic methods and delivery systems utilizing sex steroid precursors
US5861391A (en) * 1997-01-29 1999-01-19 Research Development Foundation Use of dehydroepiandrosterone to treat primary adrenal insufficiency and Addison's disease
US5955455A (en) * 1993-01-19 1999-09-21 Endorecherche, Inc. Therapeutic methods and delivery systems utilizing sex steroid precursors
WO1999063973A2 (fr) * 1998-06-11 1999-12-16 Endorecherche, Inc. COMPOSITIONS PHARMACEUTIQUES ET UTILISATIONS POUR L'ANDROST-5-ENE-3β,17β-DIOL

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5843932A (en) * 1993-01-19 1998-12-01 Endorcaherche, Inc. Therapeutic methods and delivery systems utilizing sex steroid precursors
US5955455A (en) * 1993-01-19 1999-09-21 Endorecherche, Inc. Therapeutic methods and delivery systems utilizing sex steroid precursors
US5861391A (en) * 1997-01-29 1999-01-19 Research Development Foundation Use of dehydroepiandrosterone to treat primary adrenal insufficiency and Addison's disease
WO1999063973A2 (fr) * 1998-06-11 1999-12-16 Endorecherche, Inc. COMPOSITIONS PHARMACEUTIQUES ET UTILISATIONS POUR L'ANDROST-5-ENE-3β,17β-DIOL
US6432940B1 (en) * 1998-06-11 2002-08-13 Endorecherche, Inc. Uses for androst-5-ene-3β, 17β-diol

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Title
ARLT WIEBKE ET AL.: "Dehydroepiandrosterone replacement in women with adrenal insufficiency", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 341, no. 14, 1999, pages 1013 - 1020, XP002967345 *
BURGER HENRY G.: "Androgen production in women", FERTILITY AND STERILITY, vol. 77, no. 4, SUPPL. 4, 2002, pages S3 - S5, XP002967343 *
HUNT PENELOPE J. ET AL.: "Improvement in mood and fatigue after dehydroepiandrosterone replacement Addison's disease in a randomized double blind trial", THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 85, no. 12, 2000, pages 4650 - 4656, XP002967346 *
ILONDO M.M. ET AL.: "Plasma androgens in children and adolescents", HORMONE RES., vol. 16, 1982, pages 78 - 95, XP002967344 *
JOHANNSSON ET AL.: "Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen-deficient women: a placebo-controlled trial", THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 87, no. 5, 2002, pages 2046 - 2052, XP002967339 *
MILLER KAREN K. ET AL.: "Androgen deficiency in women with hypopituitarism", THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 86, no. 2, 2001, pages 561 - 567, XP002967340 *
SESMILO GEMMA ET AL.: "Inflammatory cardiovascular risk markers in women with hypopituitarism", THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 86, no. 12, 2001, pages 5774 - 5781, XP002967341 *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112394102A (zh) * 2020-11-05 2021-02-23 上海交通大学医学院附属瑞金医院 一种检测垂体功能减退症的标志物及其应用
CN112394102B (zh) * 2020-11-05 2023-05-26 上海交通大学医学院附属瑞金医院 一种检测垂体功能减退症的标志物及其应用

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AU2003224561A1 (en) 2003-11-10

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