Pregnenolone Cream

Overview of Pregnenolone Cream

Dosage Strengths of Pregnenolone Cream

100 mg/mL 30 mL Topi-Click Dispenser

General Information

Pregnenolone, also referred to as 5-pregnenolone or pregn-5-en-3β-ol-20-one, is a 21-carbon endogenous steroid.1 It is biosynthesized from cholesterol and is a precursor and a metabolic intermediate to the gonadal steroid hormones and adrenal corticosteroids, including estrogen, progesterone, testosterone, dehydroepiandrosterone (DHEA), cortisol, and cortisone.1 2 Pregnenolone is also biosynthesized from cholesterol within the central nervous system and the peripheral nervous system, which lends its classification as a neurosteroid.3

Synthetic pregnenolone is sold as a supplement. It is not FDA-approved and there is little data on the safety and efficacy of long-term use of pregnenolone. Pregnenolone should be taken under the supervision of a physician.

Preliminary research shows that pregnenolone enhances learning and memory and can even reverse memory deficits in rodents.4 5 However, human studies have produced contradictory results.5

Initial research shows that pregnenolone has significant anti-inflammatory properties.6

Dysregulation of pregnenolone has been observed in patients with schizophrenia, bipolar disorder, depression, and Alzheimer’s disease.7 8 9 10 This data leads researchers to look at the potential of exogenous pregnenolone to treat patients with these conditions.

Early human trials show that pregnenolone significantly improves SANS scores in patients diagnosed with schizophrenia compared to placebo.4 Early human trials suggest that pregnenolone may improve depressive symptoms in patients diagnosed with bipolar disorder.11

Mechanisms of Action

Pregnenolone plays a crucial role in processes throughout the body, including neurogenic growth.12 It’s role as a substrate makes it crucial in the production of steroid hormones and adrenal corticosteroids and therefore highlights its importance in the regulation of bodily processes. It is also a precursor to other neurosteroids, including pregnenolone sulfate and allopregnanolone.13 14

As a neurosteroid, pregnenolone modulates neurotransmission via the neuronal membrane and provokes structural changes in neurons and in astrocytes.15 Neurosteroids, including pregnenolone, have a modulating effect on neural excitability and synaptic plasticity.12 Pregnenolone is an excitatory neurosteroid and can act as an allosteric modulator of neurotransmitter receptors, such as GABAA, NMDA, and sigma receptors.16 17 18

Pregnenolone is a ligand of the microtubule-associated protein 2 (MAP2) for the stimulation of the polymerization of microtubules.19 It is also a N-methyl-d-aspartate (NMDA) NMDA ligand.16 It is a negative allosteric modulator of the GABAA receptor and the CB1 receptor, and is an agonist of the σ1 receptor and the pregnane X receptor.20 21 22 23 24 25

Contraindications/Precautions

There is little data on the long-term effects of oral pregnenolone. Since pregnenolone is a precursor to estrogen, its use is contraindicated in patients diagnosed with or at risk for estrogen-dependent cancers, including breast, endometrial, ovarian, and prostate.34 35 36 37 Research shows that high levels of estrogen may also contribute to a number of health concerns and conditions, including endometriosis, cardiovascular disease, lupus erythematosus, neurodegenerative diseases like Alzheimer’s, and seizure disorders.38 39 40 41 42 43

High levels of DHEA, a pregnenolone-derived neurosteroid, might worsen psychiatric disorders and increase the risk of mania in people who have mood disorders. Pregnenolone is contraindicated in patients taking DHEA, patients with higher than normal levels of DHEA, and patients who have been diagnosed with or who are at risk for psychiatric disorders and mania.44 45

Pregnenolone may cause rapid heart beat.46 Pregnenolone is contraindicated in patients diagnosed with or at risk for arrhythmia.

Pregnenolone is contraindicated in patients diagnosed with or at risk for liver or kidney disease.

Smoking increases the risk of cardiovascular disease in women taking menopausal hormone therapy.47 48 Smoking increases testosterone levels in men by as much as 15% compared to patients who do not smoke.49 Although more research is needed to fully understand how smoking impacts hormone levels, it is recommended that patients interested in taking pregnenolone should cease smoking before taking pregnenolone.48

Pregnancy/Breastfeeding

There is little data on the use of pregnenolone tablets in women who are pregnant or breastfeeding. As such, it is difficult to determine a drug-associated risk of adverse developmental outcomes. Women who are pregnant or breastfeeding should avoid using this product.

Interactions

Pregnenolone counteracts the sedative effects of diazepam (Valium).50 Although more research is needed, this suggests that it may also counteract the sedative effects of all benzodiazepines. Furthermore, pregnenolone has been shown to produce an anxiogenic response in mice.51

Pregnenolone inhibits the GABAA receptor and may also inhibit drugs used to increase GABA activity, such as Neurontin for epilepsy and depression.46

Pregnenolone is contraindicated in patients taking DHEA. High levels of DHEA might worsen psychiatric disorders and may increase the risk of mania in people who have mood disorders.44 45

There is not enough data on the concurrent use of pregnenolone and other hormone therapies. Since pregnenolone is the precursor to steroid hormones, it may augment the effects of hormone therapy and may increase the risk and severity of side effects of hormone therapy.

Alterations in levels of downstream pregnenolone metabolites, such as estradiol, could impact the efficacy of oral contraceptives.4

Adverse Reactions/Side Effects

There is very little data on the effects of long-term use of pregnenolone. Limited studies where pregnenolone is administered for four to twelve weeks show that pregnenolone is well-tolerated.52 11 4 One study recorded mild side effects, including mild restlessness, mild muscle pain/stiffness, and mild cold extremities.4

Pregnenolone may cause side effects similar to those known for testosterone, including acne, hair loss, aggressiveness, irritability, increased levels of estrogen, and hair growth on the face in women. In some cases, which would call for immediate termination of use, it may cause rapid heartbeat, blurred vision, and dizziness.46 This list may not include all possible adverse reactions or side effects.

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond-use date. Do not flush unused medications or pour down a sink or drain.

1. a. b. Burstein S, Gut M. Biosynthesis of Pregnenolone. Recent Prog Horm Res. 1971;27:303-49.
2. Strushkevich N, MacKenzie F, Cherkesova T, Grabovec I, Usanov S, Park HW. Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system. Proc Natl Acad Sci USA. 2011;108(25):10139-43.
3. M Schumacher, P Robel, E E Baulieu. Development and regeneration of the nervous system: a role for neurosteroids. Dev Neurosci. 1996;18(1-2):6-21.
4. a. b. c. d. e. Marx CE, Keefe RSE, et al. Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia. Neuropsychopharmacology. 2009 Jul; 34(8): 1885–1903.
5. a. b. Vallée M, Mayo W, Moal ML. Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging. Brain Res Brain Res Rev. 2001 Nov;37(1-3):301-12.
6. Murugan S, Jakka P, Namani S , Mujumdar V, Radhakrishnan G. The neurosteroid, pregnenolone promotes degradation of key proteins in the innate immune signalling to suppress inflammation. 2019;294(12):4596-4607.
7. Michael Ritsner, Rachel Maayan, Anatoly Gibel, Abraham Weizman. Differences in blood pregnenolone and dehydroepiandrosterone levels between schizophrenia patients and healthy subjects. Eur Neuropsychopharmacol. 2007;17(5):358-65.
8. Marx CE, Stevens RD, Shampine LJ, et al. Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics. Neuropsychopharmacology. 2006;31(6):1249-63.
9. George MS, Guidotti A, Rubinow D, Pan B, Mikalauskas K, Post RM. CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI. Biol Psychiatry. 1994;35(10):775-80.
10. Weill-Engerer S, David JP, Sazdovitch V. Neurosteroid quantification in human brain regions: comparison between Alzheimer's and nondemented patients. J Clin Endocrinol Metab. 2002;87(11):5138-43.
11. a. b. Brown ES, Park J,1 Marx CE, et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Pregnenolone for Bipolar Depression. Neuropsychopharmacology. 2014; 39(12): 2867–2873.
12. a. b. Plassart-Schiess E, Baulieu EE. Neurosteroids: recent findings. Brain Research Reviews. 2001;37(1-3):133-140.
13. Ducharme N, Banks WA, Morley JE, Robinson SM, Niehoff ML, and Mattern C. Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration. Eur J Pharmacol. 2010; 641(2-3):128–134.
14. Sripada RK, Marx CE, King AP, Rampton JC, Ho S, Liberzon I. Allopregnanolone Elevations Following Pregnenolone Administration are Associated with Enhanced Activation of Emotion Regulation Neurocircuits. Biol Psychiatry. 2013;73(11):1045–1053.
15. Schumacher M, Robel P, Baulieu EE. Development and regeneration of the nervous system: a role for neurosteroids. Dev Neurosci. 1996;18(1-2):6-21.
16. a. b. Mellon SH. Neurosteroid regulation of CNS development. Pharmacol Ther. 2007;116(1):107–124.
17. Baulieu EE, Robel P, Schumacher M. Neurosteroids: beginning of the story. Int Rev Neurobiol. 2001;46:1-32.
18. Baulieu EE. Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Recent Prog Horm Res. 1997;52:1-32.
19. Fontaine-Lenoir V, Chambraud B, Fellous A, David S, Duchossoy Y, Baulieu EE, Robel P. Microtubule-associated protein 2 (MAP2) is a neurosteroid receptor. Proc Natl Acad Sci USA. 2006;103(12):4711–4716.
20. Wang M. Neurosteroids and GABA-A Receptor Function. Front Endocrinol (Lausanne). 2011;2:44.
21. Akk G, Bracamontes J, Steinbach JH. Pregnenolone sulfate block of GABAA receptors: mechanism and involvement of a residue in the M2 region of the α subunit. J Physiol. 2001;532(Pt 3):673–684.
22. Pertwee R.G. (2015) Endocannabinoids and Their Pharmacological Actions. In: Pertwee R. (eds) Endocannabinoids. Handbook of Experimental Pharmacology, vol 231.
23. Romieu P, Martin-Fardon R, Bowen WD, Maurice T. σ1 Receptor-Related Neuroactive Steroids Modulate Cocaine-Induced Reward. J Neurosci. 2003;23(9):3572–3576.
24. Kliewer SA, Lehmann JM, Milburn MV, Willson TM. The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways. Recent Prog Horm Res. 1999;54:345-67.
25. Ma Y, Liu D. Activation of Pregnane X Receptor by Pregnenolone 16 α-carbonitrile Prevents High-Fat Diet-Induced Obesity in AKR/J Mice. PLoS One. 2012;7(6):e38734.
34. Russo J, Russo IH. The Role of Estrogen in the Initation of Brest Cancer. J Steroid Biochem Mol Biol. 2006;102(1-5)89–96.
35. Yang B, Chen R, Liang X, Shi J, Wu X, Zhang Z, Chen X. Estrogen Enhances Endometrial Cancer Cells Proliferation by Upregulation of Prohibitin. J Cancer. 2019; 10(7):1616-1621.
36. Mungenast F, Thalhammer T. Estrogen Biosynthesis and Action in Ovarian Cancer. Front Endocrinol (Lausanne). 2014;5:192.
37. Bosland MC. The Role of Estrogens in Prostate Carcinogenesis: A Rationale for Chemoprevention. Rev Urol. 2005;7(Suppl 3):S4–S10.
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46. a. b. c. Pure Encapsulations® pregnenolone 30mg capsules package insert. 2016.
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52. Naylor JC, Kilts JD, Shampine LJ, et al. Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain Among US Military Veterans. JAMA Netw Open. 2020;3(3):e200287.

Overview of Pregnenolone Cream

Dosage Strengths of Pregnenolone Cream

General Information

Mechanisms of Action

Contraindications/Precautions

Pregnancy/Breastfeeding

Interactions

Adverse Reactions/Side Effects

Storage

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