In this emerging area of progesterone research, several research studies attest to the neuroprotective effects of progesterone, an absence of neurological side effects, and a benefit for cognitive function.

• Wright DW, Kellermann AL, Hertzberg VS, Clark PL, Frankel M, Goldstein FC, Salomone JP, Dent LL, Harris OA, Ander DS, Lowery DW, Patel MM, Denson DD, Gordon AB, Wald MM, Gupta S, Hoffman SW, Stein DG.  ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury.  Ann Emerg Med 2006 Sep 28; [Epub ahead of print]. 
  
  A neuroprotective effect of progesterone was observed in this randomized, placebo-controlled trial of very high dose, intravenous progesterone therapy given for 3 days after acute traumatic brain injury.  Only 13% of the patients died within 30 days after injury in the progesterone group, compared with 30% of the placebo group, and the progesterone group was more likely to have a moderate to good functional outcome after 30 days than the placebo group.  Even at the extremely high dose used, no serious adverse events were seen with progesterone.
  

• Gibson CL, Murphy SP. Progesterone enhances functional recovery after middle cerebral artery occlusion in male mice. J Cereb Blood Flow Metab. 2004 Jul;24(7):805-13.
  
  Differences in outcomes following ischemia have been noted between men and women, and this is thought to be attributed to sex steroids. This study investigated the potential benefits of progesterone administration after focal cerebral ischemia of the middle cerebral artery of male mice. Male mice undergoing 60-minute middle cerebral artery occlusion (MCAO) received either progesterone or vehicle following occlusion. The mice receiving progesterone had significantly reduced lesion volume (p< 0.05) when compared with the vehicle treated mice (control). Progesterone treatment also improved survival rate, weight recovery, and motor ability when compared to the control group. In addition, mice treated with progesterone demonstrated motor ability comparable to mice that did not undergo MCAO. The authors suggest the need to further investigate the mechanisms of progesterone action on recovery from cerebral injury.
  
  
• Schumacher M, Guennoun R, Robert F, Carelli C, Gago N, Ghoumari A, Gonzalez Deniselle MC, Gonzalez SL, Ibanez C, Labombarda F, Coirini H, Baulieu EE, De Nicola AF. Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination. Growth Horm IGF Res. 2004 Jun;14 Suppl A:S18-33.
  
  This paper reviews of the effects of progesterone as an autocrine/paracrine hormone in the brain. The brain, spinal cord and peripheral nerves all synthesize progesterone from the precursor, pregnenolone. Macroglial cells, including astrocytes, oligodendroglial cells and Schwann cells, also have the capacity to synthesize progesterone. This production is regulated by cellular interactions. Recent research has suggested the role progesterone plays in the brain is likely a significant one, supporting the viability of neurons and the formation of myelin sheaths. In mice and rat studies, progesterone also demonstrated a neuroprotective effect. These actions of progesterone suggest viable therapeutic possibilities for the prevention and treatment of neurodegenerative diseases, as well as for repair processes and for preserving cognitive functions with age.
  
  
• Grossman KJ, Goss CW, Stein DG. Effects of progesterone on the inflammatory response to brain injury in the rat. Brain Res. 2004 May 15;1008(1):29-39.
  
  Progesterone has a known anti-inflammatory effect. In this study, male rats treated with progesterone (4 mg/kg) and/or vehicle, were examined with respect to cellular inflammatory response to frontal cortex injury on postsurgical days 1, 3, 5, 7 and 9. The treated mice suffered significantly less edema than untreated mice, as well as showed an increase in the accumulation of activated microglia, demonstrating a neuroprotective effect on the rat brain.
  
  
• Cummings JA, Brizendine L. Comparison of physical and emotional side effects of progesterone or medroxyprogesterone in early postmenopausal women. Menopause 2002 Jul-Aug;9(4):253-63.
  
  Twenty-three early postmenopausal women were randomized to either medroxyprogesterone acetate (MPA) or oral micronized progesterone combined with conjugated equine estrogens (CEE) and followed for 91 days in a sequence of treatments. None of the hormone treatments had any noticeable effect on mood. Participants using MPA experienced more breast tenderness and bleeding than those using progesterone. This study debunks the belief that progesterone depresses mood in healthy individuals.
  
  
• de Wit H, Schmitt L, Purdy R, Hauger R. Effects of acute progesterone administration in healthy postmenopausal women and normally-cycling women. Psychoneuroendocrinology 2001 Oct;26(7):697-710.
  
  This randomized controlled study investigated the effects of acute progesterone administration (25, 50, 100 mg, intramuscularly, 1 dose/wk) on mood. Contrary to the investigators’ expectations, very few unwanted behavioral effects were noted, and only in the highest dose (100 mg) did women slightly increase their self-rating of “sluggishness”.
  
  
• Baulieu E, Schumacher M. Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination. Steroids 2000 Oct-Nov;65(10-11):605-12.
  
  This paper reviews the effects of progesterone on the brain, with special focus on its role in the formation of the myelin sheath surrounding nerve fibers. Other roles of progesterone in the brain include activating GABA receptors, which induces a calming effect.
  
  
• Mahesh VB, Brann DW, and Hendry LB. Diverse modes of action of progesterone and its metabolites. J Steroid Biochem Molec Biol 1996;56(1-6):209-219.
  
  A review of the actions of progesterone and its metabolites demonstrates physiological significance in such biological activities as may have importance in the regulation of stress, post-partum depression, memory, cognition, PMS, and depression, to name a few.
  
  
• Arafat ES, Hargrove JT, Maxson WS, Desiderio DM, Wentz AC, Andersen RN. Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites. Am J Obstet Gynecol 1988 Nov; 159(5): 1203-9.
  
  This small pilot study evaluated progesterone and its metabolites following administration of oral micronized progesterone in eight postmenopausal women. Progesterone and its metabolites were measured in serum extracts by radioimmunoassay and gas chromatography-mass spectrometry. Evaluation of serial blood samples showed elevated levels of serum progesterone and its metabolites from baseline, reaching a peak between 2 and 6 hours after oral administration. The following compounds: progesterone, 5 beta-pregnan-3 alpha, 5 alpha-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha-ol-20-one, 20 beta-diol, and 5 beta-pregnan-3 alpha-ol-11,20-dione, were identified. These compounds have reported anesthetic qualities, which may contribute to the sedative and hypnotic effects seen with oral administration of progesterone. The authors reported that, in one subject, 400 mg of oral micronized progesterone induced a hypnotic state lasting approximately 2 hours.

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