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Progestins and the Brain
Muye Zhu, B.S., and Roberta Diaz Brinton, Ph.D.

Ms. Zhu is a doctoral candidate, Neuroscience Program, College of Letters, Arts and Sciences, University of Southern California and Dr. Brinton is Professor of Pharmacology and Pharmaceutical Sciences, Biomedical Engineering and Neurology, School of Pharmacy, Viterbi USC School of Engineering and Keck USC School of Medicine, University of Southern California, Los Angeles, CA.

Within the past 12 months, Ms. Zhu and Dr. Brinton report no commercial conflicts of interest.

Albert Einstein College of Medicine, CCME staff, and interMDnet staff have nothing to disclose.


Release Date: 12/01/2011
Termination Date: 12/01/2014

Estimated time to complete: 1 hour(s).

Albert Einstein College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Albert Einstein College of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
 
Learning Objectives
Upon completion of this Cyberounds®, you should be able to:
  • Discuss the differential effects of progestins on the regenerative (neurogenic) capacity of the brain
  • Discuss the contrasting effects on brain metabolism induced by progesterone and medroxyprogesterone
  • Discuss the clinical implications of progestin regulation of brain regeneration, metabolism and white matter generation
  • Apply their understanding of the effects of long-term exposure to progestins on brain function and the chronic use of hormone therapies and contraceptives.

 

Progestins are a class of molecules composed of the naturally occurring progesterone [discovered (1930) and isolated (1933) by Willard Allen and George Corner] and synthesized steroids initially designed to block the proliferative effects of estrogen in reproductive tissues, specifically in the uterus. Several generations of clinical progestins have been synthesized and marketed for contraception and hormone therapy.

While the target of progestins used in hormone therapy is primarily the uterus, progestin therapy affects every major organ system including the brain, the cardiovascular system, the immune system and hematopoietic system.(1)(2)(3)(4)(5)(6)(7)(8) As in other systems, progestins exert unique profiles of outcomes in the brain, which ultimately could impact the long-term neurological health of users.

In contraceptive preparations, progestins are used to prevent ovulation and pregnancy and are often combined with estrogen to obtain better menstrual cycle control and more effective inhibition of follicle maturation and ovulation. The majority of contraceptive drugs currently on the market are estrogen and progestin combined oral formulations. Other formulations, including parenteral administration, implants, vaginal rings, transdermal gels and sprays have also been developed and commercialized.(9) Hormone therapy is often provided to surgically menopausal, perimenopausal and naturally postmenopausal women to alleviate the clinical symptoms caused by decline in ovarian hormones. In hormone therapy preparations, progestins are required for women with intact uterus to counter the estrogen-induced endometrial hyperplasia. The variety of hormone therapy formulations has followed that of contraceptive options (see Table 1).

Table 1. Commercially Available Contraceptive Drug and Hormone Therapy Preparations.

Hormone Therapy Drug Name Formulation Estrogen (Dose) Progestin (Dose)  
Sequential Combined Preparations Climagest Tabs Estradiol (1mg, 2mg) * Norethisterone (1mg)
Clinorette Tabs Estradiol (2mg) Norethisterone (1mg)
Cyclo-progynova Tabs Estradiol (2mg) Norgestrel (500mcg)
Elleste Duet Tabs Estradiol (1mg, 2mg) Norethisterone (1mg)
Evorel Sequi Patches Estradiol (50mcg) Norethisterone (170mcg)
Femoston Tabs Estradiol (1mg, 2mg) Dydro- gesterone (10mg)
FemSeven Sequi Patches Estradiol (50mcg) Levonorgestrel (10mcg)
Novofem Tabs Estradiol (1mg) Norethisterone (1mg)
Prempak-C</td> Tabs Conjugated estrogen (625mcg, 1.25mg) Norgestrel (150mcg)
Tridestra Tabs Estradiol (2mg) Medroxy- progesterone (20mg)
Trisequens Tabs Estradiol (2mg, 2mg, 1mg) Norethisterone (1mg)
Continuous Combined Preparations Angeliq Tabs Estradiol (1mg) Drospirenone (2mg)
Climesse Tabs Estradiol (2mg) Norethisterone (700mcg)
Elleste Duet Conti Tabs Estradiol (2mg) Norethisterone (1mg)
Evorel Conti Patches Estradiol (50mcg) Norethisterone (170mcg)
Femoston Conti Tabs Estradiol (1mg) Dydro- gesterone (5mg)
FemSeven Conti Patches Estradiol (50mcg) Levonorgestrel (7mcg)
Indivina Tabs Estradiol (1mg, 2mg) Medroxy- progesterone (2.5mg, 5mg)
Kliofem Tabs Estradiol (2mg) Norethisterone (1mg)
Kliovance Tabs Estradiol (1mg) Norethisterone (500mcg)
Nuvelle Continuous Tabs Estradiol (2mg) Norethisterone (1mg)
Premique Low Dose Tabs Conjugated oestrogen (300mcg) Medroxy- progesterone (1.5mg)
Premique Tabs Conjugated oestrogen (625mcg) Medroxy- progesterone (5mg)
Unopposed Estrogen Preparations Bedol Tabs Estradiol (2mg)

Climaval Tabs Estradiol (1mg, 2mg)

Elleste Solo Tabs Estradiol (1mg, 2mg)

Elleste Solo MX Patches Estradiol (40mcg, 80mcg)

Estraderm MX Patches Estradiol (25mcg, 50mcg, 75mcg, 100mcg)

Estraderm TTS Patches Estradiol (25mcg, 100mcg)

Estradot Patches Estradiol (25mcg, 37.5mcg, 50mcg, 75mcg, 100mcg)

Evorel Patches Estradiol (25mcg, 50mcg, 75mcg, 100mcg)

FemSeven Patches Estradiol (50mcg, 75mcg, 100mcg)

Hormonin Tabs Estradiol (0.6mg), estrone (1.4mg), estriol (0.27mg)

Premarin Tabs Conjugated oestrogen (300mcg, 625mcg, 1.25mg)

Progynova Tabs Estradiol (1mg, 2mg)

Progynova TS Patches Estradiol (50mcg, 100mcg)

Sandrena Gel Estradiol (500mcg, 1mg)

Zumenon Tabs Estradiol (1mg, 2mg)

Estring Vaginal ring Estradiol (7.5mcg)

Gynest Cream Vaginal cream Estriol (0.01%)

Vagifem Vaginal tabs Estradiol (25mcg)

Contraceptives Drug Name Formulation Estrogen (Dose) Progestin (Dose)
Combined Monophasic Preparations Gedarel 20/150 Tabs Ethiny- lestradiol (20mcg) Desogestrel (150mcg)
Gedarel 30/150 Tabs Ethiny- lestradiol (30mcg) Desogestrel (150mcg)
Marvelon Tabs Ethiny- lestradiol (30mcg) Desogestrel (150mcg)
Mercilon Tabs Ethiny- lestradiol (20mcg) Desogestrel (150mcg)
Yasmin Tabs Ethiny- lestradiol (30mcg) Drospirenone (3mg)
NuvaRing Vaginal ring Ethiny- lestradiol (15mcg) Etonogestrel (120mcg)
Femodene Tabs Ethiny- lestradiol (30mcg) Gestodene (75mcg)
Femodette Tabs Ethiny- lestradiol (20mcg) Gestodene (75mcg)
Katya Tabs Ethiny- lestradiol (30mcg) Gestodene (75mcg)
Millinette 20/75 Tabs Ethiny- lestradiol (20mcg) Gestodene (75mcg)
Millinette 30/75 Tabs Ethiny- lestradiol (30mcg) Gestodene (75mcg)
Sunya Tabs Ethiny- lestradiol (20mcg) Gestodene (75mcg)
Microgynon 30 Tabs Ethiny- lestradiol (30mcg) Levonorgestrel (150mcg)
Ovranette Tabs Ethiny- lestradiol (30mcg) Levonorgestrel (150mcg)
Rigevidon Tabs Ethiny- lestradiol (30mcg) Levonorgestrel (150mcg)
Brevinor Tabs Ethiny- lestradiol (35mcg) Norethisterone (500mcg)
Loestrin 20 Tabs Ethiny- lestradiol (20mcg) Norethisterone acetate (1mg)
Loestrin 30 Tabs Ethiny- lestradiol (30mcg) Norethisterone acetate (1.5mg)
Norimin Tabs Ethiny- lestradiol (35mcg) Norethisterone (1mg)
Ovysmen Tabs Ethiny- lestradiol (35mcg) Norethisterone (500mcg)
Cilest Tabs Ethiny- lestradiol (35mcg) Norgestimate (250mcg)
Norinyl-1 Tabs Mestranol (50mcg) Norethisterone (1mg)





# of Tabs
Combined Four-Phasic Preparation Qlaira Tabs Estradiol (3mg)
2
Estradiol (2mg) Dienogest (2mg) 5
Estradiol (2mg) Dienogest (3mg) 17
Estradiol (1mg)
2
Combined Triphasic Preparations Triadene Tabs Ethiny- lestradiol (30mcg) Gestodene (50mcg) 6
Ethiny- lestradiol (40mcg) Gestodene (70mcg) 5
Ethiny- lestradiol (30mcg) Gestodene (100mcg) 10
Logynon Tabs Ethiny- lestradiol (30mcg Levonorgestrel (50mcg) 6
Ethiny- lestradiol (40mcg) Levonorgestrel (75mcg) 5
Ethiny- lestradiol (30mcg) Levonorgestrel (125mcg) 10
TriRegol Tabs Ethiny- lestradiol (30mcg) Levonorgestrel (50mcg) 6
Ethiny- lestradiol (40mcg) Levonorgestrel (75mcg) 5
Ethiny- lestradiol (30mcg) Levonorgestrel (125mcg) 10
Synphase Tabs Ethiny- lestradiol (35mcg) Norethisterone (500mcg) 7
Ethiny- lestradiol (35mcg) Norethisterone (1mg) 9
Ethiny- lestradiol (35mcg) Norethisterone (500mcg) 5
TriNovum Tabs Ethiny- lestradiol (35mcg) Norethisterone (500mcg) 7
Ethiny- lestradiol (35mcg) Norethisterone (750mg) 7
Ethiny- lestradiol (35mcg) Norethisterone (1mg) 7
Combined Diphasic Preparation BiNovum Tabs Ethiny- lestradiol (35mcg) Norethisterone (500mcg) 7
Ethiny- lestradiol (35mcg) Norethisterone (1mg) 14
Progestin-Only Preparations Cerazette Tabs
Desogestrel (75mcg)
Norgeston Tabs
Levonorgestrel (30mcg)
Femulen Tabs
Etynodiol diacetate (500mcg)

Micronor Tabs
Norethisterone (350mcg)
Noriday Tabs
Norethisterone (350mcg)

Sequential combined hormone therapy preparations are suitable for perimenopausal women who are experiencing irregular menstrual bleeding. In these preparations, estrogen is provided throughout the whole menstrual cycle, while progestin is added only during the second half. Continuous combined hormone therapy preparations contain both estrogen and progestin at all times. The biphasic contraceptive drugs deliver 2 different doses or hormones during a complete cycle, whereas the triphasic and four-phasic contraceptive drugs deliver 3 and 4 different doses, respectively. *: Some drugs are available in multiple strengths, as indicated by the several different doses listed in brackets.

Increasing evidence indicates that progestins differentially regulate the regenerative and bioenergetic capacity of the brain alone or in combination with estrogen.(4)(5)(6)(7) Findings from these preclinical studies indicate that the type and regimen of progestin used in hormone therapy/contraception and the timing of HT intervention during the peri- to post-menopausal years could dramatically impact neurological health and cognitive function.(16)(17)(18)(19)(20)(21)(22)(23) The focus of this Cyberounds® is progestin action on the brain, specifically the impact of progestins on the regenerative and bioenergetic capacity of the brain, as well as their effects on cognition.

The interaction between progestins and [steroid] receptors is a major source of the undesired side effects...

Progesterone and Progestin Receptors In The Brain

The brain is a primary target for both contraceptive and hormone therapy where these therapies regulate the reproductive cycle and hot flushes. Progestins interact with progesterone receptors that are present both in the nucleus and on the cell membrane.(24)(25)(26) Further, depending upon the chemical structure of these molecules, progestins will also interact with estrogen, androgen, glucocorticoid and mineralocorticoid receptors. (9)(27) Receptors for progesterone and other steroid hormones are abundant in the hypothalamus as well as other brain regions not directly involved in reproductive function.(25) Specifically, these molecules regulate mitochondrial function, synaptogenesis, neurogenesis and regeneration, myelination, inflammation, mood and cognition.(4)(5)(6)(7)(28)(29)(30)(31)(32)(33)

Synthetic progestins were originally developed to overcome the short biological half-life and high production cost of progesterone.(34)(35) They are structurally derived from either progesterone or testosterone (36) and are categorized into “generations”: the first generation (medroxyprogesterone acetate, norethindrone, etc.), second generation (levonorgestrel, norgestrel, etc.), third generation (gestodene, desogestrel, norgestimate, etc.) and new generation (drospirenone).(37) Compared to third and new generations, the earlier generations of progestins often have lower progestational activity and greater interaction with other steroid receptors, i.e., the androgen, estrogen, glucocorticoid and mineralocorticoid receptors.(9)(27)

The interaction between progestins and these receptors is a major source of the undesired side effects seen in hormonal contraception and hormone therapy, of which the most disturbing are the increased risks of breast cancer and cardiovascular diseases.(1)(9)(38)(39) Newer progestins were often designed to better mimic the physiological function of progesterone and minimize the side effects by reducing the interaction between progestins and other steroid hormone receptors.(38) Systematic evaluation of efficacy and safety of these newer progestins in contraceptive and hormone replacement therapy preparations is needed to determine their long-term impact on women’s health.

Progesterone receptors are broadly expressed throughout the brain and can be detected in every neural cell type.

Emerging data indicate that progesterone has multiple non-reproductive functions in the central nervous system -- regulation of mitochondrial function, synaptogenesis, neurogenesis and regeneration, myelination, inflammation, mood and cognition.(4)(5)(6)(7)(8)(25)(31)(32)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50) Progesterone-regulated neural responses are mediated by an array of progesterone receptors that include the classic nuclear progesterone receptor A and progesterone receptor B and splice variants of each, the seven transmembrane domain 7TMPRb and the membrane-associated 25-Dx progesterone receptor PGRMC1.(25)(51)(52)(53) These progesterone receptors induce classic regulation of gene expression while also transducing signaling cascades that originate at the cell membrane and ultimately activate transcription factors. Remarkably, progesterone receptors are broadly expressed throughout the brain and can be detected in every neural cell type. The distribution of progesterone receptors beyond hypothalamic borders provides the foundation for a much broader role of progesterone in regulating neural function.(25)

Progestin Regulation of Regeneration In The Brain

Progesterone regulation of cellular proliferative activities was first recognized in reproductive tissues, most notably in the breast(54)(55) and the uterus. In breast tissue, progesterone can promote proliferation, whereas in the uterus it has both inhibitory and stimulatory effects, depending on cell type, the regimen of treatment, whether progesterone receptor A or progesterone receptor B is expressed and the dose of estrogen and progesterone.(25)

In the adult brain, proliferation of neural cells occurs in two proliferative zones, the subgranular zone of the hippocampus and the subventricular zone of the cerebral ventricles.(56)(57) The generation of new neurons (neurogenesis) occurs in both zones. As in the uterus, progesterone regulation of mitosis in the nervous system is complex. Results from multiple laboratories have indicated that progesterone regulates neural cell proliferation in both the peripheral and central nervous system.(58)(59) Preclinical analyses indicate that progesterone can act as a neurogenic agent to promote hippocampal neural progenitor cell proliferation.(6) Further, progesterone significantly increased the expression of genes required for progression through the cell cycle and inhibited expression of genes involved in repression of the cell cycle.(6) Progesterone-induced neurogenesis was a direct effect of progesterone and did not require conversion to its metabolites.

The direct effect of progesterone on neural progenitor cell proliferation was demonstrated by inhibiting the conversion of progesterone to its metabolites 5-dihydroprogesterone and allopregnanolone by finasteride.(6) Blocking the conversion of progesterone to its metabolism had no effect on progesterone-induced neural progenitor cell proliferation, demonstrating the direct effect of progesterone. Interestingly, progesterone-induced neural progenitor cell proliferation was mediated by the membrane progesterone receptor PGMRC1. The requirement of PGMRC1 was demonstrated by RNA interference (siRNA) knock-down of PGMRC1 receptor expression in rat neural progenitor cells which abolished the proliferative effect of progesterone.

Progesterone increased proliferation of neural progenitor cell from female adult rat hippocampus with maximal proliferative efficacy within the picomolar/nanomolar range, which was reversed at the higher micromolar range.(6) In the adult female rat, progesterone plasma levels range from 1 to 200 nM, and the concentration of progesterone in the brain is thought to closely follow circulating plasma levels.(60) The mitotic efficacy of progesterone was comparable to the growth factor bFGF.(62) Importantly, progesterone-induced DNA synthesis did not persist beyond 24 hours, indicating that progesterone-responsive rat neural progenitor cells traversed the cell cycle but did not remain in a proliferative state and thus progesterone, in vitro, did not induce prolonged or uncontrolled proliferation. Other groups have reported that progesterone promotes cell proliferation in both peripheral and central nervous system at nanomolar/micromolar ranges.(58)(61)

Clinical hormone therapies are often administered as a continuous combined regimen of an estrogen and progestin. Translationally, it was important to investigate the impact of the combined exposure of estrogen and progesterone on the regenerative capacity of the brain. Estrogen alone is neurogenic, as is progesterone. When progesterone was administered simultaneously with estrogen, the neurogenic effect of estrogen was antagonized.(63)

In the aged brain, both the pool of neural stem cells and their proliferative potential are markedly diminished.(64)(65)(66) The discovery that progesterone could promote adult rat neural progenitor cell proliferation highlights the potential use of progesterone as a regenerative agent in adult brain. Indeed, several studies reported that administration of progesterone could improve cognitive performance in the aging mouse when compared with control groups.(67)(68)(69) Together with our present data, these findings suggest a promising strategy for promoting neurogenesis in the adult brain. Furthermore, the finding that the estrogen receptor and PGRMC1 were mutually exclusive in breast tumor sections, and that PGRMC1 labeling increased in hypoxic areas of the tumor,(70)(71) suggests that targeting PGMRC1 may be a novel approach to promote proliferation in the brain while avoiding tumorogenic effects in estrogen receptor-positive cells.

Clinical Progestin Regulation of Regeneration in the Brain

Our group investigated the efficacy of seven clinically relevant progestins (i.e., nestorone, medroxyprogesterone, levonorgestrel, norgestimate, norethindrone, norethindrone acetate and norethynodrel) alone or in combination with estrogen on adult rat neural progenitor cell proliferation and hippocampal cell viability, a predictive indicator of the health of newly generated and existing cells in vitro and in vivo. In vitro analyses indicated that progesterone, norgestimate, nestorone, norethynodrel, norethindrone and levonorgestrel significantly increased rat neural progenitor cell BrdU (a synthetic nucleoside) incorporation, a marker for DNA synthesis and cell proliferation, while norethindrone acetate was without effect, and medroxyprogesterone acetate decreased BrdU incorporation.(5)

Since estrogen is used together with progestin in most contraceptive and hormone therapy preparations, it was critical to investigate the impact of exposure to estrogen + progestin on neurogenesis and neuroprotection. Results of these analyses showed that estrogen significantly increased neural proliferation at a magnitude comparable with that of progesterone alone. No significant differences were observed between estrogen alone, estrogen + progesterone and estrogen + nestorone groups. Both levonorgestrel and medroxyprogesterone increased BrdU+ cell count when administered in combination with estrogen.(5) However, in parallel to the increase in BrdU positive cells, levonorgestrel and medroxyprogesterone significantly increased the number of apoptotic cells(5) indicating these cells were undergoing programmed cell death, which is consistent with the proapoptotic effects of levonorgestrel and medroxyprogesterone in the uterus.(72)

Results of these studies indicate that acute exposure to clinically relevant progestins and estrogen + progestin combinations differentially regulated neurogenic and neuroprotective responses in brain. Clinical progestins exerted a range of effects that span promotion of neurogenesis and neuroprotection to inducing apoptosis and reduced cell viability. The effects of progestins were tested at clinically relevant concentrations.(5)

The differential proliferative effects of the progestins were potentially due to progestins binding to multiple steroid receptors. Indeed, levonorgestrel and norgestimate exert androgenic effects by binding to and activating the nuclear androgen receptor. However, norgestimate, in contrast to levonorgestrel, inhibits nuclear translocation of the androgen receptor, revealing an antiandrogenic property.(73) Also, norethynodrel induces estrogenic activity through aromatization in vivo. Although nestorone can bind to the nuclear glucocorticoid receptor, it showed no glucocorticoid activity in vivo.(74)(75) While these preclinical studies were limited in scope, they pointed to differential effects on the regenerative system in brain that could have profound clinical implications for neurological health in women.

Progesterone also promotes brain metabolism.

Progestin Regulation of White Matter Regeneration

The subventricular zone neurogenic niche also gives rise to oligodendrocytes, which are capable of migrating into sites of demyelination under disease or injury conditions in an attempt to repair the disrupted myelin sheath.(76) Progesterone facilitated oligodendrocyte precursor cell proliferation and differentiation, with acute treatment favoring proliferation whereas chronic administration favored differentiation.(77)(78) Oligodendrocyte death and white matter lesion is a well-characterized feature of Alzheimer’s disease.(79)(80) While progesterone was an effective remyelinating molecule under multiple disease and injury conditions(28)(81)(82)(83)(84), its potential to alleviate white matter abnormalities present in Alzheimer’s disease remains to be tested.

Progestin Regulation of Brain Metabolism

Recent data indicate that progesterone also promotes brain metabolism. Mitochondria are the primary energy producers of the cell that convert nutrients into ATP for energy through cellular respiration via the electron transport chain. Our group investigated the impact of progesterone on key mitochondrial functions, oxidative respiration and free radical generation in the central nervous system. We found that both estrogen and progesterone significantly increased mitochondrial respiration 24 hours after a single in vivo exposure.(7) Neither progesterone nor estrogen nor their combination induced evidence for mitochondrial biogenesis, indicating these effects were due to progesterone and estrogen regulation of mitochondrion function rather than an increase in mitochondrial number.(7) Together, these preclinical data revealed that the gonadal hormones progesterone and estrogen were potent regulators of mitochondrial function to increase both the magnitude and efficiency of mitochondrial respiration in brain.

Further, both estrogen and progesterone reduced free radical leak, indicating greater efficiency of electron transport. Consistent with reduced generation of free radicals, progesterone and estrogen induced a significant reduction in mitochondrial lipid peroxidation. Oxidative damage to mitochondria is posited to play a major role in aging and in neuronal populations may underlie cognitive declines associated with aging.(85)(86)(87) As electrons pass through the mitochondrial electron transport chain, some electrons leak out to molecular oxygen (O2) to form O2•−, which is dismutated (simultaneous reduction and oxidation creating two different compounds) by manganese superoxide dismutase (MnSOD) to form hydrogen peroxide (H2O2). The hydrogen peroxide can in turn be reduced to water by peroxidases such as glutathione peroxidase or peroxiredoxins.

A lack of sufficient peroxidase activity results in the peroxidation of lipids and proteins. Lipid peroxidation, the nonspecific oxidation of polyunsaturated fatty acids in cellular membranes, is a radical-mediated pathway and generates a number of harmful degradation products besides drastically altering the structure and function of the membrane. Our results demonstrated that ovarian hormone treatment reduced lipid peroxidation of whole-brain mitochondria. This result is consistent with previous reports demonstrating that estrogen(88)(89)(90) and progesterone(91) could individually reduce oxidative stress in the brain.

Surprising...lack of synergy when progesterone and estrogen were administered in combination.

Respiratory control is one facet of an interlocking network regulating metabolic activity and energy production in which mitochondrial redox potential is coupled with cytosolic signaling. This tightly coupled network integrates various signals to determine cell fate based upon ATP levels, extracellular signals and energetic demands. In addition to the defensive effects of estrogen and progesterone, including regulation of the Bcl-2 family proteins,(92) the increased respiratory control efficiency and decreased oxidative load demonstrated in this study could establish a buffer, an antioxidant defense against neuronal functional decline associated with aging and neurodegenerative diseases.

Surprising to us was the lack of synergy when progesterone and estrogen were administered in combination. On all outcome measures, the combination of progesterone and estrogen resulted in a substantial decrement in response magnitude. Another point of note is that the effects of the combined treatment were not consistent across all outcome measures. In some outcomes, as in mitochondrial respiration, there was no effect of the combined treatment relative to control, and in others, as in cytochrome c oxidase activity and expression, the combined treatment significantly altered the response relative to control.(7) Thus, the neuroprotective abilities of combined estrogen and progesterone do not involve all aspects of mitochondrial bioenergetics, and the two steroids probably act through two different sets of overlapping sets of mechanisms. These distinct mechanisms may act synergistically or antagonistically resulting in the mixed profile of outcomes.

Clinical Progestin Regulation of Brain Metabolism

The impact of clinical progestins used in contraception and hormone therapies on the metabolic capacity of the brain has long-term implications for neurological health in pre- and postmenopausal women.

In preclinical models, ovariectomized female rats were treated with medroxyprogesterone, estrogen, estrogen + medroxyprogesterone or placebo, with ovary-intact rats serving as a positive control. Medroxyprogesterone alone and medroxyprogesterone + estrogen resulted in diminished mitochondrial protein levels for pyruvate dehydrogenase, cytochrome oxidase, ATP synthase, manganese-superoxide dismutase and peroxiredoxin V.(4) Medroxyprogesterone alone did not rescue the ovariectomy-induced decrease in mitochondrial bioenergetic function, whereas the co-administration of estrogen and medroxyprogesterone exhibited moderate efficacy.(4) However, the co-administration of medroxyprogesterone was detrimental to antioxidant defense, including manganese-superoxide dismutase activity/expression and peroxiredoxin V expression.(4)

As mentioned above, estrogen, progesterone, or co-administration reduced electron leak, indicating greater efficiency of electron transport.(7) Consistent with reduced generation of free radicals, estrogen completely prevented mitochondrial lipid peroxidation. In contrast, medroxyprogesterone or estrogen + medroxyprogesterone combination did not prevent ovariectomy-induced lipid peroxidation. Furthermore, medroxyprogesterone abolished estrogen-induced enhancement of mitochondrial respiration in primary cultures of the hippocampal neurons and glia (4). In vivo analyses of multiple clinically relevant progestins confirmed that progesterone, nestorone, and levonorgestrel induced a significant rise in mitochondrial CVα expression, a marker of cell viability, whereas medroxyprogesterone showed no effect, indicating the neuroprotective effects of the progestins are closely related to their ability in regulating mitochondria function.

Collectively these findings demonstrate that the effects of medroxyprogesterone differ significantly from the bioenergetic profile induced by progesterone and that, overall, medroxyprogesterone induced a decline in glycolytic and oxidative phosphorylation protein and activity. On all outcome measures except respiration, the combination of medroxyprogesterone and estrogen was not synergistic and when administered in combination led to a decreased response relative to estrogen alone. Findings from this study provide insights into progestin regulation of mitochondrial respiration and the impact of clinical regimens of hormone therapy on mitochondrial function in the brain. A major challenge now is to identify a selective progestin that is best suited for hormone therapy outcomes in brain, including sustaining cognitive function with age.

Progestin Regulation of Cognitive Function

While there have been an abundance of studies investigating the cognitive outcomes of combined estrogen + progestin hormone therapy/contraceptive use in women, the exact effects of progestins on cognition remain elusive. The Women’s Health Initiative Memory Study (WHIMS), the largest randomized, controlled study of the kind, found that the conjugated equine estrogen + metroxyprogesterone treated group of women had higher risk of probable, all-cause dementia compared to the conjugated equine estrogen only group and the placebo group.(14)(15) Estrogen has been shown to have multiple beneficial effects on brain metabolism and cognition, capable of increasing dendritic spine density and enhancing synaptic plasticity in the hippocampus, elevating brain mitochondrial efficiency and preventing metabolic decline in postmenopausal women, notably in brain regions most susceptible to Alzheimer’s disease, and protecting against oxidative stress as well as β-amyloid-induced neuronal apoptosis.(10)(92)(93)(94)(95) The discrepancies between these studies and findings from WHIMS led to the speculation that progestins may affect aspects of cognition negatively, attenuating or opposing the beneficial effects of estrogen.

Several important issues, however, were not addressed in the WHIMS study and they must be considered to better understand the true impact of progestins on cognition. First, most researchers investigating cognitive outcomes of combined hormone therapy/contraceptive used estrogen + medroxyprogesterone preparations.(20)(96) Medroxyprogesterone is reported in many preclinical and clinical studies to have detrimental biological properties. Its strong androgenic effect is associated with increased risk of breast cancer in hormone therapy users.(39)(97) In the brain, medroxyprogesterone antagonizes the estrogen up-regulation of mitochondrial function and is bioenergetically inhibitory by itself.(4) Long term weekly treatment with medroxyprogesterone causes working memory impairment.(50)

Because of its widespread use medroxyprogesterone has been extensively studied but much less is known about the variety of progestins used in the hormone therapy/contraceptive preparations listed in Table 1. Indeed, several studies reported favorable effects on cognition by alternative progestins. Post-menopausal women receiving conjugated equine estrogen + micronized progesterone for 12 weeks performed significantly better on a working memory task than the conjugated equine estrogen + medroxyprogesterone and the conjugated equine estrogen + placebo groups.(32) The preclinical data are consistent with the clinical data. Rats treated with progesterone, alone or in conjunction with estrogen, had improved cognitive behavior.(67)(68)(69) Importantly, women who used contraceptive drugs with new generation progestin performed better on mental rotation (a task in which subjects are presented with two objects, often each rotated a specific amount of degrees, and must decide whether the two objects are identical or mirror images) and verbal fluency than women using contraceptive drugs with third generation progestins,(98) further supporting the postulate that progestins modulate cognition differentially.

In preclinical studies, the regimen of progestin administration, in particular the continuous vs. cyclic paradigm, can affect the cognitive outcome. In an ovariectomized female mouse model of Alzheimer’s disease, estrogen reduced amyloid pathology and improved working memory. A hormone regimen of cyclic progesterone + estrogen enhanced the beneficial effects of estrogen including reducing amyloid pathology.(99) In contrast, continuous progesterone treatment antagonized the beneficial effects of estrogen.(99) These preclinical data comparing the impact of cyclic vs. continuous exposure to progesterone have potential clinical implications, as the majority of hormone therapies use a continuous combined regimen of treatment (see Table 1).

Discussion

Clinical progestins are an integral constituent of contraceptive and hormone therapy preparations. Progestin-containing contraceptive drugs account for an increasing proportion of modern contraceptive formulations used by women around the world. In the United Kingdom, the commercially popular progestins are 19-nortestosterone derivatives (norethindrone acetateA, norgestrel and levonorgestrel). In France, micronized progesterone and 19-norprogesterone (such as promegestone and nomegestrol acetate) are commonly prescribed, while medroxyprogesterone is the most prescribed progestin in the United States(5) and the progestin used in commonly randomized controlled hormone therapy trials including the Women’s Health Initiative(100) and Women’s Health Initiative Memory Study.(15)(19) Typically, clinical progestins are chronically administered, extending over many years to decades. For example, depomedroxyprogesterone acetate, a long-acting formulation of medroxyprogesterone, is extensively prescribed for adolescent females,(101) and Norplant implant delivers constant infusion of levonorgestrel for 5–7 years.(102)

Despite the global clinical use of progestins, little is known regarding the impact of chronic exposure to these molecules in the brains of women during and following their reproductive years. Preclinical research from our laboratory and others strongly suggest that these molecules have profound effects on neurological functions that range from regeneration in the brain to cognition. These effects could have implications for protection against or vulnerability to neurodegenerative diseases and warrant further intensive investigation.

Summary

Progestins are a class of molecules composed of the naturally occurring progesterone and synthesized steroids initially designed to block the proliferative effects of estrogen in reproductive tissues, specifically in the uterus. In addition to regulating the reproductive system, progestins impact multiple major organ systems including the brain. We and others have found that progestins have differential effects on brain regeneration, brain metabolism and cognitive function when administered alone or in combination with estrogen. Progesterone has a favorable profile of action in the brain, promoting regeneration and mitochondrial function. Under certain conditions, progesterone can improve cognitive performance. In contrast, synthesized progestins have a mixed profile of outcomes in the brain that span from beneficial to detrimental. Both preclinical and clinical data raise concern on the type and regimen of progestins currently used in hormone therapy and contraceptive preparations, and partially explain the variability observed in outcomes in brain at both the preclinical and clinical levels of analyses. Given the wide use of hormone and contraceptive therapies worldwide, understanding progestin regulation of brain function and cognition has the potential to profoundly impact women's neurological health.

Acknowledgement

The works reviewed here were supported by National Institute on Aging Grant 1 PO1 AG026572 (to R.D.B.).


Footnotes

1Sitruk-Ware, R. and A. Nath, Metabolic effects of contraceptive steroids. Rev Endocr Metab Disord, 2011. 12(2): p. 63-75.
2Dressing, G.E., et al., Membrane progesterone receptor expression in mammalian tissues: a review of regulation and physiological implications. Steroids, 2011. 76(1-2): p. 11-7.
3Tait, A.S., C.L. Butts, and E.M. Sternberg, The role of glucocorticoids and progestins in inflammatory, autoimmune, and infectious disease. J Leukoc Biol, 2008. 84(4): p. 924-31.
4Irwin, R.W., et al., Medroxyprogesterone acetate antagonizes estrogen up-regulation of brain mitochondrial function. Endocrinology, 2011. 152(2): p. 556-67.
5Liu, L., et al., Clinically relevant progestins regulate neurogenic and neuroprotective responses in vitro and in vivo. Endocrinology, 2010. 151(12): p. 5782-94.
6Liu, L., et al., Progesterone increases rat neural progenitor cell cycle gene expression and proliferation via extracellularly regulated kinase and progesterone receptor membrane components 1 and 2. Endocrinology, 2009. 150(7): p. 3186-96.
7Irwin, R.W., et al., Progesterone and estrogen regulate oxidative metabolism in brain mitochondria. Endocrinology, 2008. 149(6): p. 3167-75.
8Brinton, R.D. and J. Nilsen, Effects of estrogen plus progestin on risk of dementia. JAMA, 2003. 290(13): p. 1706; author reply 1707-8.
9Sitruk-Ware, R. and A. Nath, The use of newer progestins for contraception. Contraception, 2010. 82(5): p. 410-7.
10Brinton, R.D., Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Sci, 2009. 30(4): p. 212-22.
14Espeland, M.A., et al., Conjugated equine estrogens and global cognitive function in postmenopausal women: Women's Health Initiative Memory Study. JAMA, 2004. 291(24): p. 2959-68.
15Shumaker, S.A., et al., Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA, 2004. 291(24): p. 2947-58.
16Henderson, V.W., Aging, estrogens, and episodic memory in women. Cogn Behav Neurol, 2009. 22(4): p. 205-14.
17Maki, P.M., Hormone therapy and cognitive function: is there a critical period for benefit? Neuroscience, 2006. 138(3): p. 1027-30.
18Morrison, J.H., et al., Estrogen, menopause, and the aging brain: how basic neuroscience can inform hormone therapy in women. J Neurosci, 2006. 26(41): p. 10332-48.
19Resnick, S.M., et al., The Women's Health Initiative Study of Cognitive Aging (WHISCA): a randomized clinical trial of the effects of hormone therapy on age-associated cognitive decline. Clin Trials, 2004. 1(5): p. 440-50.
20Sherwin, B.B., Estrogen therapy: is time of initiation critical for neuroprotection? Nat Rev Endocrinol, 2009. 5(11): p. 620-7.
21Sherwin, B.B. and J.F. Henry, Brain aging modulates the neuroprotective effects of estrogen on selective aspects of cognition in women: a critical review. Front Neuroendocrinol, 2008. 29(1): p. 88-113.
22Whitmer, R.A., et al., Timing of hormone therapy and dementia: the critical window theory revisited. Ann Neurol, 2011. 69(1): p. 163-9.
23Wroolie, T.E., et al., Differences in verbal memory performance in postmenopausal women receiving hormone therapy: 17beta-estradiol versus conjugated equine estrogens. Am J Geriatr Psychiatry, 2011. 19(9): p. 792-802.
24Thomas, P., Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol, 2008. 29(2): p. 292-312.
25Brinton, R.D., et al., Progesterone receptors: form and function in brain. Front Neuroendocrinol, 2008. 29(2): p. 313-39.
26Mitterling, K.L., et al., Cellular and subcellular localization of estrogen and progestin receptor immunoreactivities in the mouse hippocampus. J Comp Neurol, 2010. 518(14): p. 2729-43.
27Africander, D., N. Verhoog, and J.P. Hapgood, Molecular mechanisms of steroid receptor-mediated actions by synthetic progestins used in HRT and contraception. Steroids, 2011. 76(7): p. 636-52.
28Hussain, R., et al., Progesterone and Nestorone facilitate axon remyelination: a role for progesterone receptors. Endocrinology, 2011. 152(10): p. 3820-31.
29El-Etr, M., et al., Hormonal influences in multiple sclerosis: new therapeutic benefits for steroids. Maturitas, 2011. 68(1): p. 47-51.
30Zhao, Y., et al., Progesterone influences postischemic synaptogenesis in the CA1 region of the hippocampus in rats. Synapse, 2011. 65(9): p. 880-91.
31Tournell, C.E., R.A. Bergstrom, and A. Ferreira, Progesterone-induced agrin expression in astrocytes modulates glia-neuron interactions leading to synapse formation. Neuroscience, 2006. 141(3): p. 1327-38.
32Sherwin, B.B. and M. Grigorova, Differential effects of estrogen and micronized progesterone or medroxyprogesterone acetate on cognition in postmenopausal women. Fertil Steril, 2011. 96(2): p. 399-403.
33Henderson, V.W., Gonadal hormones and cognitive aging: a midlife perspective. Womens Health (Lond Engl). 7(1): p. 81-93.
34Ganjam, V.K., R.M. Kenney, and G. Flickinger, Effect of exogenous progesterone on its endogenous levels: biological half-life of progesterone and lack of progesterone binding in mares. J Reprod Fertil Suppl, 1975(23): p. 183-8.
35Dhont, M., History of oral contraception. Eur J Contracept Reprod Health Care, 2010. 15 Suppl 2: p. S12-8.
36Stanczyk, F.Z., All progestins are not created equal. Steroids, 2003. 68(10-13): p. 879-90.
37Benagiano, G., S. Carrara, and V. Filippi, Safety, efficacy and patient satisfaction with continuous daily administration of levonorgestrel/ethinylestradiol oral contraceptives. Patient Prefer Adherence, 2009. 3: p. 131-43.
38Sitruk-Ware, R., New progestagens for contraceptive use. Hum Reprod Update, 2006. 12(2): p. 169-78.
39Ghatge, R.P., et al., The progestational and androgenic properties of medroxyprogesterone acetate: gene regulatory overlap with dihydrotestosterone in breast cancer cells. Breast Cancer Res, 2005. 7(6): p. R1036-50.
40McEwen, B.S. and C.S. Woolley, Estradiol and progesterone regulate neuronal structure and synaptic connectivity in adult as well as developing brain. Exp Gerontol, 1994. 29(3-4): p. 431-6.
41Tsutsui, K., Progesterone biosynthesis and action in the developing neuron. Endocrinology, 2008. 149(6): p. 2757-61.
42Wang, J., et al., Progesterone inhibits inflammatory response pathways after permanent middle cerebral artery occlusion in rats. Mol Med Report. 4(2): p. 319-24.
43Georgiadou, P. and E. Sbarouni, Effect of hormone replacement therapy on inflammatory biomarkers. Adv Clin Chem, 2009. 47: p. 59-93.
44Garay, L., et al., Progesterone attenuates demyelination and microglial reaction in the lysolecithin-injured spinal cord. Neuroscience. 192: p. 588-97.
45Johansson, A.G., et al., AKR1C4 gene variant associated with low euthymic serum progesterone and a history of mood irritability in males with bipolar disorder. J Affect Disord, 2011. 133(1-2): p. 346-51.
46Sherwin, B.B., The impact of different doses of estrogen and progestin on mood and sexual behavior in postmenopausal women. J Clin Endocrinol Metab, 1991. 72(2): p. 336-43.
47Kang, J.H. and F. Grodstein, Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiol Aging, 2010.
48Alhola, P., et al., Estrogen + progestin therapy and cognition: a randomized placebo-controlled double-blind study. J Obstet Gynaecol Res, 2010. 36(4): p. 796-802.
49Sun, W.L., et al., Acute progesterone treatment impairs spatial working memory in intact male and female rats. Ethn Dis, 2010. 20(1 Suppl 1): p. S1-83-7.
50Braden, B.B., et al., Cognitive-impairing effects of medroxyprogesterone acetate in the rat: independent and interactive effects across time. Psychopharmacology (Berl), 2011. 218(2): p. 405-18.
51Conneely, O.M., et al., The A and B forms of the chicken progesterone receptor arise by alternate initiation of translation of a unique mRNA. Biochem Biophys Res Commun, 1987. 149(2): p. 493-501.
52Zhu, Y., et al., Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc Natl Acad Sci U S A, 2003. 100(5): p. 2231-6.
53Falkenstein, E., et al., Specific progesterone binding to a membrane protein and related nongenomic effects on Ca2+-fluxes in sperm. Endocrinology, 1999. 140(12): p. 5999-6002.
54Chlebowski, R.T., et al., Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA, 2003. 289(24): p. 3243-53.
55Pike, M.C. and R.K. Ross, Progestins and menopause: epidemiological studies of risks of endometrial and breast cancer. Steroids, 2000. 65(10-11): p. 659-64.
56van Praag, H., et al., Functional neurogenesis in the adult hippocampus. Nature, 2002. 415(6875): p. 1030-4.
57Arvidsson, A., et al., Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med, 2002. 8(9): p. 963-70.
58Magnaghi, V., et al., Progesterone derivatives increase expression of Krox-20 and Sox-10 in rat Schwann cells. J Mol Neurosci, 2007. 31(2): p. 149-57.
59Ghoumari, A.M., E.E. Baulieu, and M. Schumacher, Progesterone increases oligodendroglial cell proliferation in rat cerebellar slice cultures. Neuroscience, 2005. 135(1): p. 47-58.
60Butcher, R.L., W.E. Collins, and N.W. Fugo, Plasma concentration of LH, FSH, prolactin, progesterone and estradiol-17beta throughout the 4-day estrous cycle of the rat. Endocrinology, 1974. 94(6): p. 1704-8.
61Marin-Husstege, M., et al., Oligodendrocyte progenitor proliferation and maturation is differentially regulated by male and female sex steroid hormones. Dev Neurosci, 2004. 26(2-4): p. 245-54.
62Wang, J.M., L. Liu, and R.D. Brinton, Estradiol-17beta-induced human neural progenitor cell proliferation is mediated by an estrogen receptor beta-phosphorylated extracellularly regulated kinase pathway. Endocrinology, 2008. 149(1): p. 208-18.
63Tanapat, P., N.B. Hastings, and E. Gould, Ovarian steroids influence cell proliferation in the dentate gyrus of the adult female rat in a dose- and time-dependent manner. J Comp Neurol, 2005. 481(3): p. 252-65.
64Kuhn, H.G., H. Dickinson-Anson, and F.H. Gage, Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci, 1996. 16(6): p. 2027-33.
65Villeda, S.A., et al., The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature, 2011. 477(7362): p. 90-4.
66Enwere, E., et al., Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci, 2004. 24(38): p. 8354-65.
67Frye, C.A. and A.A. Walf, 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, 2008. 90(1): p. 171-7.
68Frye, C.A. and A.A. Walf, Progesterone enhances performance of aged mice in cortical or hippocampal tasks. Neurosci Lett, 2008. 437(2): p. 116-20.
69Frye, C.A. and A.A. Walf, Effects of progesterone administration and APPswe+PSEN1Deltae9 mutation for cognitive performance of mid-aged mice. Neurobiol Learn Mem, 2008. 89(1): p. 17-26.
70Crudden, G., R. Loesel, and R.J. Craven, Overexpression of the cytochrome p450 activator hpr6 (heme-1 domain protein/human progesterone receptor) in tumors. Tumour Biol, 2005. 26(3): p. 142-6.
71Craven, R.J., PGRMC1: a new biomarker for the estrogen receptor in breast cancer. Breast Cancer Res, 2008. 10(6): p. 113.
72Vereide, A.B., et al., Bcl-2, BAX, and apoptosis in endometrial hyperplasia after high dose gestagen therapy: a comparison of responses in patients treated with intrauterine levonorgestrel and systemic medroxyprogesterone. Gynecol Oncol, 2005. 97(3): p. 740-50.
73Paris, F., et al., Antiandrogenic activity of norgestimate in a human androgen-dependent stable-transfected cell line. Gynecol Endocrinol, 2007. 23(4): p. 193-7.
74Kumar, N., et al., Nestorone: a progestin with a unique pharmacological profile. Steroids, 2000. 65(10-11): p. 629-36.
75Schindler, A.E., et al., Classification and pharmacology of progestins. Maturitas, 2008. 61(1-2): p. 171-80.
76Jablonska, B., et al., Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination. Nat Neurosci, 2010. 13(5): p. 541-50.
77Labombarda, F., et al., Progesterone attenuates astro- and microgliosis and enhances oligodendrocyte differentiation following spinal cord injury. Exp Neurol, 2011. 231(1): p. 135-46.
78Labombarda, F., et al., Effects of progesterone on oligodendrocyte progenitors, oligodendrocyte transcription factors, and myelin proteins following spinal cord injury. Glia, 2009. 57(8): p. 884-97.
79Ihara, M., et al., Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer's disease, and dementia with Lewy bodies. Acta Neuropathol, 2010. 119(5): p. 579-89.
80Desai, M.K., et al., Early oligodendrocyte/myelin pathology in Alzheimer's disease mice constitutes a novel therapeutic target. Am J Pathol, 2010. 177(3): p. 1422-35.
81Yu, H.J., et al., Progesterone attenuates neurological behavioral deficits of experimental autoimmune encephalomyelitis through remyelination with nucleus-sublocalized Olig1 protein. Neurosci Lett, 2010. 476(1): p. 42-5.
82Garay, L., et al., Progesterone attenuates demyelination and microglial reaction in the lysolecithin-injured spinal cord. Neuroscience, 2011. 192: p. 588-97.
83Schumacher, M., et al., Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination. Growth Horm IGF Res, 2004. 14 Suppl A: p. S18-33.
84Schumacher, M., et al., Progesterone: therapeutic opportunities for neuroprotection and myelin repair. Pharmacol Ther, 2007. 116(1): p. 77-106.
85Barja, G., Free radicals and aging. Trends Neurosci, 2004. 27(10): p. 595-600.
86Calabrese, V., et al., Mitochondrial involvement in brain function and dysfunction: relevance to aging, neurodegenerative disorders and longevity. Neurochem Res, 2001. 26(6): p. 739-64.
87Reddy, P.H., Mitochondrial oxidative damage in aging and Alzheimer's disease: implications for mitochondrially targeted antioxidant therapeutics. J Biomed Biotechnol, 2006. 2006(3): p. 31372.
88Behl, C., et al., 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem Biophys Res Commun, 1995. 216(2): p. 473-82.
89Kii, N., et al., Acute effects of 17beta-estradiol on oxidative stress in ischemic rat striatum. J Neurosurg Anesthesiol, 2005. 17(1): p. 27-32.
90Shea, T.B. and D. Ortiz, 17 beta-estradiol alleviates synergistic oxidative stress resulting from folate deprivation and amyloid-beta treatment. J Alzheimers Dis, 2003. 5(4): p. 323-7.
91Subramanian, M., et al., Gestation confers temporary resistance to peroxidation in the maternal rat brain. Neurosci Lett, 1993. 155(2): p. 151-4.
92Nilsen, J., et al., Estrogen protects neuronal cells from amyloid beta-induced apoptosis via regulation of mitochondrial proteins and function. BMC Neurosci, 2006. 7: p. 74.
93Rasgon, N.L., et al., Estrogen use and brain metabolic change in postmenopausal women. Neurobiol Aging, 2005. 26(2): p. 229-35.
94Nilsen, J., et al., Estradiol in vivo regulation of brain mitochondrial proteome. J Neurosci, 2007. 27(51): p. 14069-77.
95Goodman, Y., et al., Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury, and amyloid beta-peptide toxicity in hippocampal neurons. J Neurochem, 1996. 66(5): p. 1836-44.
96Yesufu, A., S. Bandelow, and E. Hogervorst, Meta-analyses of the effect of hormone treatment on cognitive function in postmenopausal women. Womens Health (Lond Engl), 2007. 3(2): p. 173-94.
97Bentel, J.M., et al., Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells. Mol Cell Endocrinol, 1999. 154(1-2): p. 11-20.
98Griksiene, R. and O. Ruksenas, Effects of hormonal contraceptives on mental rotation and verbal fluency. Psychoneuroendocrinology, 2011. 36(8): p. 1239-48.
99Carroll, J.C., et al., Continuous and cyclic progesterone differentially interact with estradiol in the regulation of Alzheimer-like pathology in female 3xTransgenic-Alzheimer's disease mice. Endocrinology, 2010. 151(6): p. 2713-22.
100Rossouw, J.E., et al., Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA, 2002. 288(3): p. 321-33.
101Khoiny, F.E., Use of depo-provera in teens. J Pediatr Health Care, 1996. 10(5): p. 195-201.
102Kovalevsky, G. and K. Barnhart, Norplant and other implantable contraceptives. Clin Obstet Gynecol, 2001. 44(1): p. 92-100.