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Allopregnanolone and mood: studies of postmenopausal women during treatment with progesterone
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Introduction. Allopregnanolone and pregnanolone (neuroactive metabolites of progesterone) act as positive modulators of the GABAA receptor system which is the major inhibitory system in CNS. Contradictory results on the effect of GABAA receptor modulators are reported. Beneficial properties such as anaesthesia, sedation, and anxiolysis are reported as well as adverse, anxiogenic and aggressive effects. It has been suggested that GABAA receptor agonists have bimodal effects. Low concentrations increase an adverse, anxiogenic effect, whereas higher concentrations show beneficial, calming properties.

Aims. To investigate if progesterone treatment induces adverse mood in postmenopausal women and if the severity in mood symptoms is related to progesterone, allopregnanolone or pregnanolone serum concentrations. To evaluate differences in steroid concentrations induced by different doses and routes of administration of progesterone.

Methods. Two randomised, placebo-controlled, double-blind crossover studies of postmenopausal women were performed. Subjects were treated with estradiol continuously. Different doses of progesterone, given vaginally or orally, were added sequentially during the last 14 days of each treatment cycle. Daily symptom ratings were kept using a validated rating scale. Blood samples for progesterone, allopregnanolone and pregnanolone analyses were collected during each treatment cycle. A study regarding the pharmacokinetics after ingestion of low-dose oral progesterone was conducted with postmenopausal women. Blood samples for the analyses of progesterone, allopregnanolone and pregnanolone were collected and pharmacokinetic parameters were calculated.

Results. Certain postmenopausal women on sequential HT with vaginal and oral progesterone experience mood deterioration during the progesterone phase while on a low dose of progesterone but not on higher doses or the placebo. Negative mood symptoms occurred when the serum concentration of allopregnanolone was similar to endogenous luteal phase levels, whereas lower and higher concentrations had no effect on mood. Pharmacokinetic analyses show that low-dose oral progesterone can be used as a prodrug to allopregnanolone when the aim is to achieve physiological concentrations of allopregnanolone.

Conclusions. A bimodal association between allopregnanolone concentration and adverse mood is observed in postmenopausal women treated with progesterone. The addition of low-dose progesterone to estradiol induces adverse mood in postmenopausal women, whereas higher doses and placebo have no mood-deteriorating effect.

Place, publisher, year, edition, pages
Umeå: Klinisk vetenskap , 2006. , 142 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1022
Keyword [en]
Obstetrics and gynaecology, Progesterone, Allopregnanolone, GABA, mood, bimodal
Keyword [sv]
Obstetrik och kvinnosjukdomar
Identifiers
URN: urn:nbn:se:umu:diva-785ISBN: 91-7264-065-0 (print)OAI: oai:DiVA.org:umu-785DiVA: diva2:144527
Public defence
2006-06-01, hörsal Betula, 6M, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2006-05-03 Created: 2006-05-03 Last updated: 2011-04-07Bibliographically approved
List of papers
1. Progesterone effects during sequential hormone replacement therapy
Open this publication in new window or tab >>Progesterone effects during sequential hormone replacement therapy
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2003 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 148, no 5, 571-577 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-5130 (URN)12720542 (PubMedID)
Available from: 2006-05-03 Created: 2006-05-03 Last updated: 2015-11-11Bibliographically approved
2. Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone.
Open this publication in new window or tab >>Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone.
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2005 (English)In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 30, no 2, 212-224 p.Article in journal (Refereed) Published
Keyword
Administration; Intravaginal, Adult, Affect/physiology, Cross-Over Studies, Dose-Response Relationship; Drug, Double-Blind Method, Drug Therapy; Combination, Estradiol/administration & dosage, Female, Hormone Replacement Therapy/*adverse effects/psychology, Humans, Middle Aged, Mood Disorders/blood/*chemically induced, Postmenopause/blood/*drug effects/psychology, Pregnanolone/*administration & dosage/*adverse effects/blood, Progesterone/*administration & dosage/adverse effects/blood, Severity of Illness Index
Identifiers
urn:nbn:se:umu:diva-16940 (URN)10.1016/j.psyneuen.2004.07.003 (DOI)15471618 (PubMedID)
Available from: 2007-10-22 Created: 2007-10-22 Last updated: 2011-04-12Bibliographically approved
3. Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone.
Open this publication in new window or tab >>Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone.
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2006 (English)In: Maturitas, ISSN 0378-5122, E-ISSN 1873-4111, Vol. 54, no 3, 238-244 p.Article in journal (Refereed) Published
Keyword
Administration; Oral, Adult, Aged, Area Under Curve, Estrogen Replacement Therapy, Female, Humans, Middle Aged, Postmenopause, Pregnanolone/administration & dosage/blood/pharmacokinetics, Progesterone/administration & dosage/blood/*pharmacokinetics
Identifiers
urn:nbn:se:umu:diva-10381 (URN)10.1016/j.maturitas.2005.11.005 (DOI)16406399 (PubMedID)
Available from: 2008-09-02 Created: 2008-09-02 Last updated: 2011-04-12Bibliographically approved
4. Allopregnanolone concentration and mood: a bimodal association in postmenopausal women treated with oral progesterone.
Open this publication in new window or tab >>Allopregnanolone concentration and mood: a bimodal association in postmenopausal women treated with oral progesterone.
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2006 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 187, no 2, 209-221 p.Article in journal (Refereed) Published
Keyword
Administration; Oral, Affect/*drug effects, Climacteric/*drug effects, Cross-Over Studies, Dose-Response Relationship; Drug, Double-Blind Method, Drug Administration Schedule, Drug Therapy; Combination, Estradiol/analogs & derivatives/pharmacology, Female, Hormone Replacement Therapy, Humans, Medroxyprogesterone 17-Acetate/blood/*pharmacology, Middle Aged, Pregnanolone/*blood
Identifiers
urn:nbn:se:umu:diva-16547 (URN)10.1007/s00213-006-0417-0 (DOI)16724185 (PubMedID)
Available from: 2007-10-05 Created: 2007-10-05 Last updated: 2011-04-12Bibliographically approved

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