Mechanism of adrenal suppression by high-dose medroxyprogesterone acetate in breast cancer patients

Veelen, H. van; Willemse, Pax H.B.; Sleijfer, Dt; Ploeg, Emily M.; Sluiter, Willem; Doorenbos, H

doi:10.1007/bf00257530

Cited by 36 publications

(19 citation statements)

References 21 publications

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“…Therefore, the antitumoral effects of high-dose MPA might be less derived from the progesterone receptor cascades than from cytotoxic effects on the tumor cell (12). Increased oxidative activity of 17b-hydroxysteroid dehydrogenase (25) inducing the conversion of estradiol to estrone (26), suppression of adrenal androgen synthesis and reduction in estrogens as the metabolites of the peripheral conversion (27,28), or inhibition of angiogenesis (29,30) might be relevant. The effect of MPA on intracellular SHBG could be another mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

Effect of medroxyprogesterone acetate on sex hormone-binding globulin mRNA expression in the human endometrial cancer cell line Ishikawa

Misao

Nakanishi²,

Fujimoto³

et al. 1998

European Journal of Endocrinology

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To understand the rationale of high-dose medroxyprogesterone acetate (MPA) in the treatment of welldifferentiated uterine endometrial cancers, the effect of MPA on intracellular sex hormone-binding globulin (SHBG) mRNA expression in well-differentiated uterine endometrial cancer cell line Ishikawa was determined by competitive reverse transcription-polymerase chain reaction-Southern blot analysis. Estradiol-17b (E2, 10 ¹8 mol/l) did not alter SHBG mRNA expression, but the addition of 10 ¹10 mol/l MPA increased it, while a high concentration of MPA (10 ¹6 to 10 ¹5 mol/l) with or without E2 suppressed it. Furthermore, a high dose (10 ¹6 mol/l) of chlormadinone acetate or danazol with or without E2 significantly suppressed its expression, while MPA was the most effective among the hormones tested. The effect of MPA and the other steroid hormone analogs on SHBG expression was not mediated via the progesterone receptor.These findings suggest that intracellular SHBG suppression might partly contribute to the abolition of the intracellular estrogen-dominant milieu, and may be involved as one of the mechanisms of the antitumoral effects of high-dose MPA on the development and growth of some well-differentiated endometrial cancer cells.

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Section: Discussionmentioning

confidence: 99%

Effect of medroxyprogesterone acetate on sex hormone-binding globulin mRNA expression in the human endometrial cancer cell line Ishikawa

Misao

Nakanishi²,

Fujimoto³

et al. 1998

European Journal of Endocrinology

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“…It has been suggested that in postmenopausal women MPA may exert at least part of its activity by suppression of adrenal androgen synthesis and the consequent reduction in circulating oestrogens which are derived from the peripheral conversion of these androgens (van Veelen et al, 1985a, b). The further suggestion has been made that this inhibition of adrenal steroidogenesis may explain the higher response rate found during the use of high dose progestins (van Veelen et al, 1985a).…”

Section: Discussionmentioning

confidence: 99%

The effects of low and high dose medroxyprogesterone acetate on sex steroids and sex hormone binding globulin in postmenopausal breast cancer patients

Dowsett¹,

Lal²,

Smith³

et al. 1987

Br J Cancer

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Summary The possibility that medroxypregesterone acetate (MPA) is clinically effective at least in part by its suppression of adrenal steroidogenesis and a resultant reduction of circulating oestrogen levels was investigated in 49 postmenopausal patients with advanced breast cancer. Thirty-one patients were treated with low dose MPA (100mg three times daily) and 16 patients with high dose MPA (250mg four times daily). Plasma levels of androstenedione, testosterone, oestrone and oestradiol were all significantly reduced during treatment, with the suppression being most marked for the 17fl hydroxysteroids, testosterone and oestradiol. The fall in oestradiol levels was to about 50% of pretreatment levels, but a concomitant fall in SHBG levels to less than 25% of baseline probably resulted in the fall in free, biologically active oestradiol being only to about 70-80% of pretreatment. It is unlikely that this is a major determinant of the activity of MPA in breast cancer.

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“…which induces an inhibition of the pituitary secretion of LH and FSH [3] and consequently a block on ovarian estrogen section. Furthermore MAP reduces also the peripheral conversion of androgens in es trogens [13], suppressing adrenal androgen secretion by a block of ACTH pituitary secretion. As a conse quence MAP induces an extensive and general es trogen suppression and it could therefore be suggested in the treatment of advanced breast cancer both in premenopausal and postmenopausal patients.…”

Section: Discussionmentioning

confidence: 99%

High-Dose Medroxyprogesterone Acetate versus Oophorectomy as First-Line Therapy of Advanced Breast Cancer in Premenopausal Patients

et al. 1991

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Forty premenopausal patients with advanced breast cancer entered a prospective and randomized study in which high-dose medroyxprogesterone acetate (HD MAP) and oophorectomy (OPX) were compared. All the patients were first treated for advanced disease. Twenty-two patients received HD MAP (1,000 mg b.i.d. p.o.) and 18 patients received OPX. Complete remission (CR) was achieved in 2 (9%) in the HD MAP group and in 2 (11 %) in the OPX group for a duration of 20–24 and 30–54 months respectively. Partial remission (PR) was achieved in 10 (45%) patients in the HD MAP group and in 4 (22%) patients in the OPX group for a median duration of 9 and 7 months respectively. The objective response rates (CR + PR) were 55% for the HD MAP group and 33% for the OPX group (p = 0.17). Ten patients who received OPX as first-line treatment received HD MAP when the disease progressed and were evaluable for response: PR was achieved in 6 patients (2 responders and 4 nonresponders to OPX) for a median duration of 5 months. Two out of 4 patients who received OPX at progression after objective response to HD MAP presented PR. HD MAP induced a significant decrease in pain intensity and, compared to OPX, a more frequent improvement was induced in performance status. No difference was observed between the two groups in terms of overall survival. This study shows that HD MAP is an active treatment in premenopausal patients with advanced breast cancer and that it can induce a response in some patients resistant to OPX.

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Mechanism of adrenal suppression by high-dose medroxyprogesterone acetate in breast cancer patients

Cited by 36 publications

References 21 publications

Effect of medroxyprogesterone acetate on sex hormone-binding globulin mRNA expression in the human endometrial cancer cell line Ishikawa

Effect of medroxyprogesterone acetate on sex hormone-binding globulin mRNA expression in the human endometrial cancer cell line Ishikawa

The effects of low and high dose medroxyprogesterone acetate on sex steroids and sex hormone binding globulin in postmenopausal breast cancer patients

High-Dose Medroxyprogesterone Acetate versus Oophorectomy as First-Line Therapy of Advanced Breast Cancer in Premenopausal Patients

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