Skip to main content

Advertisement

SpringerLink
Log in

Cognitive-impairing effects of medroxyprogesterone acetate in the rat: independent and interactive effects across time

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The synthetic progestin medroxyprogesterone acetate (MPA), widely used in hormone therapy (HT) and as the contraceptive Depo Provera, is implicated in detrimental cognitive effects in women. Recent evidence in aged ovariectomized (Ovx) rodents shows that short-term MPA treatment impairs cognition and alters the GABAergic system.

Objectives

Using rats, we evaluated the long-lasting cognitive and GABAergic effects of MPA administered in young adulthood (Early-MPA), modeling contraception, and how this early exposure interacts with later MPA treatment (Late-MPA), modeling HT.

Methods

Early-MPA treatment involved weekly anti-ovulatory MPA injections (3.5 mg) from 4 to 8 months of age in ovary-intact rats. At 10 months old, rats were Ovx and weekly MPA injections were re-initiated and continued throughout testing for Late-MPA treatment.

Results

On the water radial-arm maze, all MPA-treated groups showed working memory impairment compared to Controls (p < 0.05); Early + Late-MPA rats were impaired on multiple dimensions of working memory (p < 0.05). On the Morris maze, Late-MPA rats showed greater overnight forgetting compared to Controls (p < 0.05). At study conclusion, MPA was detected in serum in all MPA-treated groups except Early-MPA, confirming treatment and clearance from serum in Early-MPA rats. In animals with detectable serum MPA, higher MPA levels were associated with less dorsal-hippocampal glutamic acid decarboxylase, the synthesizing enzyme for GABA (p = 0.0059).

Conclusions

Findings suggest that MPA treatment leads to long-lasting cognitive impairments in the rodent, even in the absence of circulating MPA in animals given prior MPA treatment, which may relate to the GABAergic system. Further research defining the parameters of the negative impact of this widely used progestin on brain and cognition is warranted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • (2006) Depo Provera Prescribing Information. In: Pfizer for Professionals. Available at http://media.pfizer.com/files/products/uspi_depo_provera_contraceptive.pdf. Accessed 28 Jan 2011

  • (2009) Prempro Prescribing Information. In: Pfizer for Professionals. Available at http://www.pfizerpro.com/content/showlabeling.asp?id-133. Accessed 28 Jan 2011

  • Acosta JI, Mayer L, Talboom JS, Tsang CW, Smith CJ, Enders CK, Bimonte-Nelson HA (2009) Transitional versus surgical menopause in a rodent model: etiology of ovarian hormone loss impacts memory and the acetylcholine system. Endocrinology 150:4248–4259

    Article  PubMed  CAS  Google Scholar 

  • Bakry S, Merhi ZO, Scalise TJ, Mahmoud MS, Fadiel A, Naftolin F (2008) Depot-medroxyprogesterone acetate: an update. Arch Gynecol Obstet 278:1–12

    Article  PubMed  Google Scholar 

  • Belelli D, Herd MB (2003) The contraceptive agent Provera enhances GABA (A) receptor-mediated inhibitory neurotransmission in the rat hippocampus: evidence for endogenous neurosteroids? J Neurosci 23:10013–10020

    PubMed  CAS  Google Scholar 

  • Bhowmik T, Mukherjea M (1988) Histological changes in the ovary and uterus of rat after injectable contraceptive therapy. Contraception 37:529–538

    Article  PubMed  CAS  Google Scholar 

  • Bigrigg A, Evans M, Gbolade B, Newton J, Pollard L, Szarewski A, Thomas C, Walling M (1999) Depo Provera. Position paper on clinical use, effectiveness and side effects. Br J Fam Plann 25:69–76

    PubMed  CAS  Google Scholar 

  • Bimonte HA, Denenberg VH (1999) Estradiol facilitates performance as working memory load increases. Psychoneuroendocrinology 24:161–173

    Article  PubMed  CAS  Google Scholar 

  • Bimonte HA, Hyde LA, Hoplight BJ, Denenberg VH (2000) In two species, females exhibit superior working memory and inferior reference memory on the water radial-arm maze. Physiol Behav 70:311–317

    Article  PubMed  CAS  Google Scholar 

  • Bimonte-Nelson HA, Singleton RS, Hunter CL, Price KL, Moore AB, Granholm AC (2003) Ovarian hormones and cognition in the aged female rat: I. Long-term, but not short-term, ovariectomy enhances spatial performance. Behav Neurosci 117:1395–1406

    Article  PubMed  CAS  Google Scholar 

  • Bimonte-Nelson HA, Singleton RS, Williams BJ, Granholm AC (2004) Ovarian hormones and cognition in the aged female rat: II. Progesterone supplementation reverses the cognitive enhancing effects of ovariectomy. Behav Neurosci 118:707–714

    Article  PubMed  CAS  Google Scholar 

  • Bimonte-Nelson HA, Francis KR, Umphlet CD, Granholm AC (2006) Progesterone reverses the spatial memory enhancements initiated by tonic and cyclic oestrogen therapy in middle-aged ovariectomized female rats. Eur J Neurosci 24:229–242

    Article  PubMed  Google Scholar 

  • Braden BB, Talboom JS, Crain ID, Simard AR, Lukas RJ, Prokai L, Scheldrup MR, Bowman BL, Bimonte-Nelson HA (2010) Medroxyprogesterone acetate impairs memory and alters the GABAergic system in aged surgically menopausal rats. Neurobiol Learn Mem 93:444–453

    Article  PubMed  CAS  Google Scholar 

  • Curran HV (1986) Tranquillising memories: a review of the effects of benzodiazepines on human memory. Biol Psychol 23:179–213

    Article  PubMed  CAS  Google Scholar 

  • Diczfalusy E (1991) Contraceptive prevalence, reproductive health and our common future. Contraception 43:201–227

    Article  PubMed  CAS  Google Scholar 

  • Fajer AB, Holzbauer M, Newport HM (1971) The contribution of the adrenal gland to the total amount of progesterone produced in the female rat. J Physiol 214:115–126

    PubMed  CAS  Google Scholar 

  • Freedman MA (2002) Quality of life and menopause: the role of estrogen. J Womens Health (Larchmt) 11:703–718

    Article  Google Scholar 

  • Freeman EW, Weinstock L, Rickels K, Sondheimer SJ, Coutifaris C (1992) A placebo-controlled study of effects of oral progesterone on performance and mood. Br J Clin Pharmacol 33:293–298

    PubMed  CAS  Google Scholar 

  • Frye CA, Sturgis JD (1995) Neurosteroids affect spatial/reference, working, and long-term memory of female rats. Neurobiol Learn Mem 64:83–96

    Article  PubMed  CAS  Google Scholar 

  • Frye CA, Walf AA (2008) Progesterone to ovariectomized mice enhances cognitive performance in the spontaneous alternation, object recognition, but not placement, water maze, and contextual and cued conditioned fear tasks. Neurobiol Learn Mem 90:171–177

    Article  PubMed  CAS  Google Scholar 

  • Frye CA, Duffy CK, Walf AA (2007) Estrogens and progestins enhance spatial learning of intact and ovariectomized rats in the object placement task. Neurobiol Learn Mem 88:208–216

    Article  PubMed  CAS  Google Scholar 

  • Frye CA, Koonce CJ, Walf AA (2010) Mnemonic effects of progesterone to mice require formation of 3alpha, 5alpha-THP. Neuroreport 21:590–595

    Article  PubMed  CAS  Google Scholar 

  • Gabriel A, Fahim G (2005) Do depot medroxyprogesterone acetate contraceptive injections cause mood changes and memory impairment? Prim Psychiatry 12:59–60

    Google Scholar 

  • Goldman JM, Murr AS, Cooper RL (2007) The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies. Birth Defects Res B Dev Reprod Toxicol 80:84–97

    Article  PubMed  CAS  Google Scholar 

  • Hani D, Imthurn B, Merki-Feld GS (2009) Weight gain due to hormonal contraception: myth or truth? Gynäkol Geburtshilfliche Rundsch 49:87–93

    Article  PubMed  Google Scholar 

  • Harburger LL, Pechenino AS, Saadi A, Frick KM (2008) Post-training progesterone dose-dependently enhances object, but not spatial, memory consolidation. Behav Brain Res 194:174–180

    Article  PubMed  CAS  Google Scholar 

  • Hersh AL, Stefanick ML, Stafford RS (2004) National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA 291:47–53

    Article  PubMed  CAS  Google Scholar 

  • Isserow JA, Rucinski B, Romero DF, Mann GN, Liu CC, Epstein S (1995) The effect of medroxyprogesterone acetate on bone metabolism in the oophorectomized, tamoxifen-treated rat. Endocrinology 136:713–719

    Article  PubMed  CAS  Google Scholar 

  • Johansson IM, Birzniece V, Lindblad C, Olsson T, Backstrom T (2002) Allopregnanolone inhibits learning in the Morris water maze. Brain Res 934:125–131

    Article  PubMed  CAS  Google Scholar 

  • Kask K, Backstrom T, Nilsson LG, Sundstrom-Poromaa I (2008) Allopregnanolone impairs episodic memory in healthy women. Psychopharmacol Berl 199:161–168

    Article  CAS  Google Scholar 

  • Keppel G, Wickens TD (2004) Design and analysis: a researcher’s handbook, 4th edn. Pearson Prentice Hall, Upper Saddle River

    Google Scholar 

  • Lang I, Zielinski CC, Templ H, Spona J, Geyer G (1990) Medroxyprogesterone acetate lowers plasma corticotropin and cortisol but does not suppress anterior pituitary responsiveness to human corticotropin releasing factor. Cancer 66:1949–1953

    Article  PubMed  CAS  Google Scholar 

  • Lewis MC, Orr PT, Frick KM (2008) Differential effects of acute progesterone administration on spatial and object memory in middle-aged and aged female C57BL/6 mice. Horm Behav 54:455–462

    Article  PubMed  CAS  Google Scholar 

  • Lowry NC, Pardon LP, Yates MA, Juraska JM (2010) Effects of long-term treatment with 17 beta-estradiol and medroxyprogesterone acetate on water maze performance in middle aged female rats. Horm Behav 58:200–207

    Article  PubMed  CAS  Google Scholar 

  • Markham JA, Pych JC, Juraska JM (2002) Ovarian hormone replacement to aged ovariectomized female rats benefits acquisition of the Morris water maze. Horm Behav 42:284–293

    Article  PubMed  CAS  Google Scholar 

  • Markowska AL (1999) Sex dimorphisms in the rate of age-related decline in spatial memory: relevance to alterations in the estrous cycle. J Neurosci 19:8122–8133

    PubMed  CAS  Google Scholar 

  • McAuley JW, Kroboth PD, Stiff DD, Reynolds IJ (1993) Modulation of [3H]flunitrazepam binding by natural and synthetic progestational agents. Pharmacol Biochem Behav 45:77–83

    Article  PubMed  CAS  Google Scholar 

  • Morris RG, Garrud P, Rawlins JN, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683

    Article  PubMed  CAS  Google Scholar 

  • Mosher WD, Martinez GM, Chandra A, Abma JC, Willson SJ (2004) Use of contraception and use of family planning services in the United States: 1982–2002. Adv Data (350):1–36

  • Nilsen J, Brinton RD (2002) Impact of progestins on estrogen-induced neuroprotection: synergy by progesterone and 19-norprogesterone and antagonism by medroxyprogesterone acetate. Endocrinology 143:205–212

    Article  PubMed  CAS  Google Scholar 

  • Nilsen J, Morales A, Brinton RD (2006) Medroxyprogesterone acetate exacerbates glutamate excitotoxicity. Gynecol Endocrinol 22:355–361

    Article  PubMed  CAS  Google Scholar 

  • Orr PT, Lewis MC, Frick KM (2009) Dorsal hippocampal progesterone infusions enhance object recognition in young female mice. Pharmacol Biochem Behav 93:177–182

    Article  PubMed  CAS  Google Scholar 

  • Pandey SC, Zhang D, Mittal N, Nayyar D (1999) Potential role of the gene transcription factor cyclic AMP-responsive element binding protein in ethanol withdrawal-related anxiety. J Pharmacol Exp Ther 288:866–878

    PubMed  CAS  Google Scholar 

  • Paris JJ, Walf AA, Frye CA (2010) II. Cognitive performance of middle-aged female rats is influenced by capacity to metabolize progesterone in the prefrontal cortex and hippocampus. Brain Res 1379:149–163

    Article  PubMed  Google Scholar 

  • Paul SM, Purdy RH (1992) Neuroactive steroids. FASEB J 6:2311–2322

    PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic, New York

    Google Scholar 

  • Pazol K, Northcutt KV, Patisaul HB, Wallen K, Wilson ME (2009) Progesterone and medroxyprogesterone acetate differentially regulate alpha4 subunit expression of GABA (A) receptors in the CA1 hippocampus of female rats. Physiol Behav 97:58–61

    Article  PubMed  CAS  Google Scholar 

  • Penning TM, Sharp RB, Krieger NR (1985) Purification and properties of 3 alpha-hydroxysteroid dehydrogenase from rat brain cytosol. Inhibition by nonsteroidal anti-inflammatory drugs and progestins. J Biol Chem 260:15266–15272

    PubMed  CAS  Google Scholar 

  • Pridjian G, Schmit V, Schreiber J (1987) Medroxyprogesterone acetate: receptor binding and correlated effects on steroidogenesis in rat granulosa cells. J Steroid Biochem 26:313–319

    Article  PubMed  CAS  Google Scholar 

  • Prokai L, Frycak P, Stevens SM, Nguyen V (2008) Measurement of acetylcholine in rat brain microdialysates by LC-isotope dilution tandem MS. Chromatographia 68:s101–s105

    Article  PubMed  CAS  Google Scholar 

  • Raol YH, Zhang G, Budreck EC, Brooks-Kayal AR (2005) Long-term effects of diazepam and phenobarbital treatment during development on GABA receptors, transporters and glutamic acid decarboxylase. Neuroscience 132:399–407

    Article  PubMed  CAS  Google Scholar 

  • Rasband W (1997–2004) Image J National Institute of Health, Bethesda, Maryland, USA. Available at http://rsb.info.nih.gov/ij/

  • Rodriguez MI, Kaunitz AM (2009) An evidence-based approach to postpartum use of depot medroxyprogesterone acetate in breastfeeding women. Contraception 80:4–6

    Article  PubMed  CAS  Google Scholar 

  • Roof RL, Hall ED (2000) Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J Neurotrauma 17:367–388

    Article  PubMed  CAS  Google Scholar 

  • Roof RL, Duvdevani R, Stein DG (1993) Gender influences outcome of brain injury: progesterone plays a protective role. Brain Res 607:333–336

    Article  PubMed  CAS  Google Scholar 

  • Sandi C, Loscertales M, Guaza C (1997) Experience-dependent facilitating effect of corticosterone on spatial memory formation in the water maze. Eur J Neurosci 9:637–642

    Article  PubMed  CAS  Google Scholar 

  • Savonenko AV, Markowska AL (2003) The cognitive effects of ovariectomy and estrogen replacement are modulated by aging. Neuroscience 119:821–830

    Article  PubMed  CAS  Google Scholar 

  • Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN 3rd, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 289:2651–2662

    Article  PubMed  CAS  Google Scholar 

  • Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH (2004) Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 291:2947–2958

    Article  PubMed  CAS  Google Scholar 

  • Smith DC, Prentice R, Thompson DJ, Herrmann WL (1975) Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 293:1164–1167

    Article  PubMed  CAS  Google Scholar 

  • Sofuoglu M, Mouratidis M, Mooney M (2011) Progesterone improves cognitive performance and attenuates smoking urges in abstinent smokers. Psychoneuroendocrinology 36:123–132

    Article  PubMed  CAS  Google Scholar 

  • Spencer AL, Bonnema R, McNamara MC (2009) Helping women choose appropriate hormonal contraception: update on risks, benefits, and indications. Am J Med 122:497–506

    Article  PubMed  Google Scholar 

  • Stefanick ML (2005) Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration. Am J Med 118(Suppl 12B):64–73

    Article  PubMed  Google Scholar 

  • Sun WL, Luine VN, Zhou L, Wu HB, Weierstall KM, Jenab S, Quiniones-Jenab V (2010) Acute progesterone treatment impairs spatial working memory in intact male and female rats. Ethn Dis 20(S1):83–87

    Google Scholar 

  • Talboom JS, Williams BJ, Baxley ER, West SG, Bimonte-Nelson HA (2008) Higher levels of estradiol replacement correlate with better spatial memory in surgically menopausal young and middle-aged rats. Neurobiol Learn Mem 90:155–163

    Article  PubMed  CAS  Google Scholar 

  • Walf AA, Rhodes ME, Frye CA (2006) Ovarian steroids enhance object recognition in naturally cycling and ovariectomized, hormone-primed rats. Neurobiol Learn Mem 86:35–46

    Article  PubMed  CAS  Google Scholar 

  • Wallis CJ, Luttge WG (1980) Influence of estrogen and progesterone on glutamic acid decarboxylase activity in discrete regions of rat brain. J Neurochem 34:609–613

    Article  PubMed  CAS  Google Scholar 

  • Warren SG, Juraska JM (2000) Sex differences and estropausal phase effects on water maze performance in aged rats. Neurobiol Learn Mem 74:229–240

    Article  PubMed  CAS  Google Scholar 

  • Ziel HK, Finkle WD (1975) Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 293:1167–1170

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was funded by grants awarded to HAB-N from the National Institute on Aging (AG028084), state of Arizona, ADHS and the Arizona Alzheimer’s Disease Core Center. LP recognizes support by the NIH Grant AG027956 and an endowment (BK-0031) from the Welch Foundation. We are grateful to Dr. Xiaoqian Liu for performing the LC–APCI-MS/MS assay and to Dr. Craig Enders for his expert statistical consultation. The authors have nothing to disclose regarding financial disclosures. The experiments comply with the current laws of the country in which they were performed.

Author information

Authors and Affiliations

  1. Department of Psychology, Arizona State University, P.O. Box 871104, Tempe, AZ, 85287, USA

    B. Blair Braden, Alexandra N. Garcia, Sarah E. Mennenga, Stephanie R. Villa, Jazmin I. Acosta & Heather A. Bimonte-Nelson

  2. Arizona Alzheimer’s Consortium, Tempe, AZ, USA

    B. Blair Braden, Sarah E. Mennenga, Jazmin I. Acosta & Heather A. Bimonte-Nelson

  3. University of North Texas Health Science Center, Fort Worth, TX, USA

    Laszlo Prokai

  4. Center for Metabolic Biology, Arizona State University, Tempe, AZ, 85287, USA

    Natalie Lefort

  5. Barrow Neurological Institute, Phoenix, AZ, USA

    Alain R. Simard

Authors
  1. B. Blair Braden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandra N. Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarah E. Mennenga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laszlo Prokai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephanie R. Villa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jazmin I. Acosta
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Natalie Lefort
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alain R. Simard
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Heather A. Bimonte-Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heather A. Bimonte-Nelson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Braden, B.B., Garcia, A.N., Mennenga, S.E. et al. Cognitive-impairing effects of medroxyprogesterone acetate in the rat: independent and interactive effects across time. Psychopharmacology 218, 405–418 (2011). https://doi.org/10.1007/s00213-011-2322-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2322-4

Keywords

Search

Navigation