Recurrent Secretion of Progesterone in Large Amounts: An Endocrine/Metabolic Disorder Unique to Young Women?*

Pc, MacDonald; Ra, Dombroski; Ml, Casey

doi:10.1210/edrv-12-4-372

Cited by 59 publications

(29 citation statements)

References 109 publications

(122 reference statements)

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“…20a-DH-P is of special interest because it is one of the major progesterone metabolites in the human kidney (19,20) and other organs (21). In addition, 20a-DH-P reaches very high serum concentrations (up to 90 nmol/l) during the third trimester of pregnancy (49).…”

Section: A-dh-p and Hmrmentioning

confidence: 99%

“…3a,5a-Tetrahydro-progesterone (3a,5a-TH-P) and 3a,5b-TH-P are ligands for the gamma-aminobutyric acid A receptor and have anesthetic, anxiolytic and anticonvulsant potency (21)(22)(23)(24). 5b-Dihydro(DH)-P reduces myometrial contractions (25) and shows pyrogenic effects (21). 5a-DH-P stimulates cell growth in a mammary tumor cell line and reduces tumor cell adhesion, whereas 3a-DH-P inhibits tumor cell growth (26).…”

Section: Introductionmentioning

confidence: 99%

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Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor

Quinkler

Meyer

Bumke-Vogt

et al. 2002

European Journal of Endocrinology

117

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Objective: Progesterone binds to the human mineralocorticoid receptor (hMR) with nearly the same affinity as do aldosterone and cortisol, but confers only low agonistic activity. It is still unclear how aldosterone can act as a mineralocorticoid in situations with high progesterone concentrations, e.g. pregnancy. One mechanism could be conversion of progesterone to inactive compounds in hMR target tissues. Design: We analyzed the agonist and antagonist activities of 16 progesterone metabolites by their binding characteristics for hMR as well as functional studies assessing transactivation. Methods: We studied binding affinity using hMR expressed in a T7-coupled rabbit reticulocyte lysate system. We used co-transfection of an hMR expression vector together with a luciferase reporter gene in CV-1 cells to investigate agonistic and antagonistic properties. Results: Progesterone and 11b-OH-progesterone (11b-OH-P) showed a slightly higher binding affinity than cortisol, deoxycorticosterone and aldosterone. 20a-dihydro(DH)-P, 5a-DH-P and 17a-OH-P had a 3-to 10-fold lower binding potency. All other progesterone metabolites showed a weak affinity for hMR. 20a-DH-P exhibited the strongest agonistic potency among the metabolites tested, reaching 11.5% of aldosterone transactivation. The agonistic activity of 11b-OH-P, 11a-OH-P and 17a-OH-P was 9, 5.1 and 4.1% respectively. At a concentration of 100 nmol/l, progesterone, 17a-OH-P and 20a-DH-P inhibit nearly 75, 40 and 35% of the transactivation by aldosterone respectively. All other progesterone metabolites tested demonstrate weaker affinity, and agonistic and antagonistic potency. Conclusions: The binding affinity for hMR and the agonistic and antagonistic activity diminish with increasing reduction of the progesterone molecule at C20, C17 and at ring A. We assume that progesterone metabolism to these compounds is a possible protective mechanism for hMR. 17a-OH-P is a strong hMR antagonist and could exacerbate mineralocorticoid deficiency in patients with congenital adrenal hyperplasia.

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Section: A-dh-p and Hmrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor

Quinkler

Meyer

Bumke-Vogt

et al. 2002

European Journal of Endocrinology

117

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“…Progesterone secretion is dramatically reduced prior to menstruation or following childbirth. These periods of progesterone clearance have been called "progesterone withdrawal" (PWD), and are associated with dynamic (but species-dependent) biological events in females (MacDonald et al, 1991). Given the temporal Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of progesterone metabolism mimics the effect of progesterone withdrawal on forced swim test immobility

Beckley¹,

Finn²

2007

Pharmacology Biochemistry and Behavior

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Withdrawal from high levels of progesterone in rodents has been proposed as a model for premenstrual syndrome or postpartum depression. Forced swim test (FST) immobility, used to model depression, was assessed in intact female DBA/2J mice following progesterone withdrawal (PWD) or treatment with the 5α-reductase inhibitor finasteride. Following 5 daily progesterone injections (5 mg/kg IP) FST immobility increased only in mice withdrawn for 3 days (p < .05). In another experiment, 3 days of PWD significantly decreased levels of progesterone compared to 0 days of withdrawal, but progesterone levels at 3 days of PWD did not differ from vehicle-treated controls. In a final study, mice received daily injections of progesterone (5 mg/kg IP) for 8 days, with 0 mg/ kg, 50 mg/kg, or 100 mg/kg finasteride co-administered for the last three days. Mice that received 100 mg/kg finasteride, but not 50 mg/kg finasteride, displayed increased FST immobility. PWD and finasteride treatment, both of which reduce allopregnanolone levels, were associated with increased FST immobility in female DBA/2J mice. These findings suggest that decreased levels of the GABAergic neurosteroid allopregnanolone contributes to symptoms of PWD. Future studies of PWD may provide information about human conditions that are associated with hormone changes such as premenstrual syndrome or postpartum depression. KeywordsDepression; premenstrual syndrome; postpartum depression; progesterone withdrawal; behavioral despair; GABA-A receptor; allopregnanolone; finasteride Beginning in adolescence, females experience affective disorders at higher rates than males, partially due to sex-specific disorders such as premenstrual syndrome (PMS) and postpartum depression (McGrath et al., 1990,Steiner et al., 2003. Progesterone secretion is dramatically reduced prior to menstruation or following childbirth. These periods of progesterone clearance have been called "progesterone withdrawal" (PWD), and are associated with dynamic (but species-dependent) biological events in females (MacDonald et al., 1991). Given the temporal Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. association between PWD and PMS or postpartum depression, studies that elucidate the effects of PWD may lead to increased understanding of these disorders. NIH Public AccessEmerging evidence about the cellular actions of progesterone and its metabolites in the brain has stimulated research regarding neuroendocrine correlates of behaviors. In addition to the actions of progesterone on intracellular and membrane-bound receptors, progesterone can be metaboli...

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“…In primates, recent studies suggest that progesterone is a mandatory mediator in ovulation [4,5] and maintenance of luteal architecture [6]. The major source of progesterone synthesis in nonpregnant women is the corpus luteum (CL), a gland that produces more than ten times its own weight of progesterone during one day in the mid luteal phase (LP) [7]. In classical sex steroid-sensitive tissues, estrogen and progesterone regulate progesterone receptors (PRs).…”

Section: Introductionmentioning

confidence: 99%

A Putative Stimulatory Role of Progesterone Acting via Progesterone Receptors in the Steroidogenic Cells of the Human Corpus Luteum1

Ottander

Hosokawa

Liu

et al. 2000

Biology of Reproduction

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To further explore the proposed auto-regulatory role of progesterone action in the human corpus luteum (CL), the expression and functional roles of progesterone receptor (PR) isoforms A and B during the luteal phase (LP) of the menstrual cycle were investigated. A total of 27 otherwise healthy patients previously scheduled for surgery were recruited after informed consent. An LH rise was detected, and CL were grouped according to age (Days 2-5 post-LH-rise, early LP; Days 6-10, mid LP; Days 11-14, late LP). Using a semiquantitative reverse transcription-polymerase chain reaction assay, the PR-B mRNA levels, which were 100- to 1000-fold lower than PR-A/B mRNA, were 46% lower (P < 0.05, n = 24) in mid LP, compared to early and late LP. CL tissue levels of progesterone and PR-A/B protein levels were inversely correlated to increasing CL age; i.e., significantly reduced levels were observed in the late LP (r(2) = 0.34, P < 0.01, n = 23). Expression of PR-A/B mRNA as well as PR-A/B protein were detected by in situ hybridization and immunohistochemistry, respectively. Both methods revealed a clear and distinct localization to cells in the steroidogenic layer of the CL. Freshly obtained mid-luteal CL cells were cultured in vitro, and media were analyzed for progesterone concentrations after treatment by incremental doses of hCG and the stable PR antagonist mifepristone, alone or in combination. Mifepristone did not per se alter progesterone synthesis, but when it was added in conjunction with hCG, a dose-related inhibitory response was seen, with a maximal 47% reduction in progesterone output at a 10 microM addition (P < 0.05, n = 3). Collectively, these data implicate a stimulatory role of progesterone receptor-mediated action in the steroidogenic cells of the human CL, which may serve as an important pathway for maintaining functional homeostasis during early pregnancy.

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Recurrent Secretion of Progesterone in Large Amounts: An Endocrine/Metabolic Disorder Unique to Young Women?*

Cited by 59 publications

References 109 publications

Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor

Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor

Inhibition of progesterone metabolism mimics the effect of progesterone withdrawal on forced swim test immobility

A Putative Stimulatory Role of Progesterone Acting via Progesterone Receptors in the Steroidogenic Cells of the Human Corpus Luteum1

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