Pregnenolone and Progesterone: A Review of Their Roles in Reproductive Health, Sleep, Growth, Neurological Function, and Idiopathic Scoliosis
Main Article Content
Abstract
Pregnenolone and progesterone are essential steroid hormones that govern numerous physiological processes across the human lifespan. Traditionally viewed as reproductive hormones, their influence extends well beyond fertility and pregnancy, shaping neurological activity, sleep patterns, bone development, and even neuromotor control. In recent years, research has suggested that deficiencies or dysregulation of these hormones may contribute to adolescent idiopathic scoliosis (IS), a complex spinal condition of uncertain origin. This review synthesizes current scientific findings, highlighting the multifaceted roles of pregnenolone and progesterone and their potential therapeutic implications for both general health and spinal deformity prevention.
Article Details
How to Cite
MORNINGSTAR, Mark.
Pregnenolone and Progesterone: A Review of Their Roles in Reproductive Health, Sleep, Growth, Neurological Function, and Idiopathic Scoliosis.
Medical Research Archives, [S.l.], v. 13, n. 9, sep. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6901>. Date accessed: 07 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i9.6901.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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36. Carp HJ, Toder V. The role of progesterone in recurrent pregnancy loss. Clin Obstet Gynecol. 2016;59:456-463.
37. Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with a short cervix (≤25 mm) in the midtrimester decreases preterm birth and neonatal morbidity: a systematic review and meta-analysis of individual patient data. Am J Obstet Gynecol. 2012;206:124.e1-124.e19.
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40. Mui Lam P, Chun Cheung M, Ping Cheung L, Ingrid Lok H, John Haines C. Effects of early luteal-phase vaginal progesterone supplementation on the outcome of in vitro fertilization and embryo transfer. Gynecol Endocrinol. 2008;24:674-80.
41. Belelli D, Lambert JJ. Neurosteroids: Endogenous regulators of the GABA_A receptor. Nat Rev Neurosci. 2005;6:565-575.
42. Shechter A, Boivin DB. Sleep, hormones, and circadian rhythms throughout the menstrual cycle in healthy women and those with premenstrual dysphoric disorder. Int J Endocrinol. 2010;2010: 259345.
43. de Zambotti M, Willoughby AR, Sassoon SA, Colrain IM, Baker FC. Menstrual cycle-related variation in physiologic sleep in women in the early menopausal transition. J Clin Endocrinol Metab. 2015;100:2918-2926.
44. Mayo W, Le Moal M, Abrous DN. Pregnenolone sulfate and aging of cognitive functions: behavioral, neurochemical, and morphological investigations. Horm Behav. 2001;40:215-7.
45. Paul SM, Purdy RH. Neuroactive steroids. FASEB J. 1992;6:2311-2322.
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57. Zheng S, Zhou H, Gao B, Li Y, Liao Z, Zhou T, Lian C, Wu Z, Su D, Wang T, Su P, Xu C. Estrogen promotes the onset and development of idiopathic scoliosis via disproportionate endochondral ossification of the anterior and posterior column in a bipedal rat model. Exp Mol Med. 2018;50:1-11.
58. Almeida M, Laurent MR, Dubois V, Claessens F, O'Brien CA, Bouillon R, Vanderschueren D, Manolagas SC. Estrogens and Androgens in Skeletal Physiology and Pathophysiology. Physiol Rev. 2017;97:135-187.
59. Wang W, Hayami T, Kapila S. Female hormone receptors are differentially expressed in mouse fibrocartilages. Osteoarthritis Cartilage. 2009;17: 646-654.
60. Fernandez-Bermejo E, García-Jiménez MA, Fernandez-Palomeque C, Munuera L. Adolescent idiopathic scoliosis and joint laxity: a study with somatosensory evoked potentials. Spine 1993;18 (7):918-922.
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64. Park Y, Ko JY, Jang JY, Lee S, Beom J, Ryu JS. Asymmetrical activation and asymmetrical weakness as two different mechanisms of adolescent idiopathic scoliosis. Sci Rep. 2021;11:17582.
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2. Stanczyk FZ. All progestins are not created equal. Steroids. 2003;68:879-890.
3. Practice Committee of the American Society for Reproductive Medicine. Progesterone supplementation during IVF: a guideline. Fertil Steril. 2015;103:e1-e9.
4. Fatemi HM, Popovic-Todorovic B, Papanikolaou E, Donoso P, Devroey P. An update of luteal phase support in stimulated IVF cycles. Hum Reprod Update. 2007;13:581-590.
5. Reddy DS. Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res. 2010;186:113-137.
6. Baker FC, Driver HS. Circadian rhythms, sleep, and the menstrual cycle. Sleep Med. 2007;8:613-622.
7. Friess E, Tagaya H, Trachsel L, Holsboer F, Rupprecht R. Progesterone-induced changes in sleep in male subjects. Am J Physiol. 1997;272: E885-E891.
8. Gava G, Orsili I, Alvisi S, Mancini I, Seracchioli R, Meriggiola MC. Cognition, mood, and sleep in menopausal transition: the role of hormone therapy. Medicina (Kaunas). 2019;55:668.
9. Mayo W, Le Moal M, Abrous DN. Pregnenolone sulfate and aging of cognitive functions: behavioral, neurochemical, and morphological investigations. Horm Behav. 2001;40:215-217.
10. Vallée M, Mayo W, Darnaudéry M, et al. Neurosteroids: deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus. Proc Natl Acad Sci U S A. 1997;94:14865-14870.
11. Schumacher M, Guennoun R, Stein DG, De Nicola AF. Progesterone: therapeutic opportunities for neuroprotection and myelin repair. Pharmacol Ther. 2007;116:77-106.
12. Marx CE, Shampine LJ, Khisti RT, et al. Olanzapine and fluoxetine administration increase pregnenolone, allopregnanolone, and deoxycorticosterone: implications for therapy. Pharmacol Biochem Behav. 2006;84:609-617.
13. Stein DG, Wright DW. Progesterone in the clinical treatment of acute traumatic brain injury. Expert Opin Investig Drugs. 2010;19:847-857.
14. Burwell RG, Dangerfield PH, Freeman BJ. Etiologic theories of idiopathic scoliosis: somatic nervous system and the NOTOM escalator concept. Stud Health Technol Inform. 2008;140:208-217.
15. Sikes-Keilp C, Rubinow DR. GABAergic modulators: new therapeutic approaches to premenstrual dysphoric disorder. CNS Drugs. 2023;37:679-693.
16. Maurice T, Urani A, Phan VL, Romieu P. The interaction between neuroactive steroids and the sigma1 receptor function: behavioral consequences and therapeutic opportunities. Brain Res Brain Res Rev. 2001;37:116-132.
17. Wu J, Qiu Y, Zhang L, Sun Q, Qiu X, He Y. Association of estrogen receptor gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2006;31:1131-1136.
18. Morningstar MW, Strauchman MN. Salivary progesterone levels in female patients with a history of idiopathic scoliosis: a retrospective cross-sectional study. Clin Pract. 2022;12:326-332.
19. Morningstar MW, DuRussel B. Differences in pubertal curve progression among females with adolescent idiopathic scoliosis using pregnenolone therapy: a retrospective case-controlled series. J Clin Med. 2024;13:788.
20. Wang W, Hayami T, Kapila S. Female hormone receptors are differentially expressed in mouse fibrocartilages. Osteoarthritis Cartilage. 2009;17: 646-654.
21. Gregoire FM, Smas CM, Sul HS. Understanding adipocyte differentiation. Physiol Rev. 1998;78:783-809.
22. Zhang HQ, Lu SJ, Tang MX, et al. Association of estrogen receptor beta gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. Spine 2009;34:760-764.
23. Fernandez-Bermejo E, García-Jiménez MA, Fernandez-Palomeque C, Munuera L. Adolescent idiopathic scoliosis and joint laxity: a study with somatosensory evoked potentials. Spine 1993;18: 918-922.
24. Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev. 2014;35:851-905.
25. Fatemi HM, Popovic-Todorovic B, Papanikolaou E, Donoso P, Devroey P. An update of luteal phase support in stimulated IVF cycles. Hum Reprod Update. 2007;13:581-590.
26. Arck PC, Hecher K. Fetomaternal immune cross-talk and its consequences for maternal and offspring’s health. Nat Med. 2013;19:548-556.
27. Fritz MA, Speroff L. Clinical Gynecologic Endocrinology and Infertility. 8th ed. Wolters Kluwer; 2011.
28. Vaisbuch E, de Ziegler D, Leong M, Weissman A, Shoham Z. Luteal-phase support in assisted reproduction treatment: real-life practices reported worldwide by an updated website-based survey. Reprod Biomed Online. 2014;28:330-5.
29. van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev. 2015:CD009154.
30. Ortega I, García-Velasco JA, Pellicer A. Ovarian manipulation in ART: going beyond physiological standards to provide best clinical outcomes. J Assist Reprod Genet. 2018;35:1751-1762.
31. Watters M, Noble M, Child T, Nelson S. Short versus extended progesterone supplementation for luteal phase support in fresh IVF cycles: a systematic review and meta-analysis. Reprod Biomed Online. 2020;40:143-150.
32. Çulcu EA, Demiryürek Ş, Demiryürek AT. An update on approved and emerging drugs for the treatment of postpartum depression. Ideggyogy Sz. 2024;77:227-235.
33. Tambe SS, Nandedkar TD. Steroidogenesis in sheep ovarian antral follicles in culture: time course study and supplementation with a precursor. Steroids. 1993;58:379-83.
34. Mesiano S, Welsh TN. Steroid hormone control of myometrial contractility and parturition. Semin Cell Dev Biol. 2007;18:321-331.
35. Haas DM, Hathaway TJ, Ramsey PS. Progestogen for preventing miscarriage. Cochrane Database Syst Rev. 2019;CD003511.
36. Carp HJ, Toder V. The role of progesterone in recurrent pregnancy loss. Clin Obstet Gynecol. 2016;59:456-463.
37. Romero R, Nicolaides K, Conde-Agudelo A, et al. Vaginal progesterone in women with a short cervix (≤25 mm) in the midtrimester decreases preterm birth and neonatal morbidity: a systematic review and meta-analysis of individual patient data. Am J Obstet Gynecol. 2012;206:124.e1-124.e19.
38. Hoff JD, Quigley ME, Yen SS. Hormonal dynamics at midcycle: a reevaluation. J Clin Endocrinol Metab. 1983;57:792-796.
39. Dušková M, Kolátorová L, Šimková M, Šrámková M, Malíková M, Horáčková L, Vítků J, Stárka L. Steroid diagnostics of 21st century in the light of their new roles and analytical tools. Physiol Res. 2020;69:S193-S203.
40. Mui Lam P, Chun Cheung M, Ping Cheung L, Ingrid Lok H, John Haines C. Effects of early luteal-phase vaginal progesterone supplementation on the outcome of in vitro fertilization and embryo transfer. Gynecol Endocrinol. 2008;24:674-80.
41. Belelli D, Lambert JJ. Neurosteroids: Endogenous regulators of the GABA_A receptor. Nat Rev Neurosci. 2005;6:565-575.
42. Shechter A, Boivin DB. Sleep, hormones, and circadian rhythms throughout the menstrual cycle in healthy women and those with premenstrual dysphoric disorder. Int J Endocrinol. 2010;2010: 259345.
43. de Zambotti M, Willoughby AR, Sassoon SA, Colrain IM, Baker FC. Menstrual cycle-related variation in physiologic sleep in women in the early menopausal transition. J Clin Endocrinol Metab. 2015;100:2918-2926.
44. Mayo W, Le Moal M, Abrous DN. Pregnenolone sulfate and aging of cognitive functions: behavioral, neurochemical, and morphological investigations. Horm Behav. 2001;40:215-7.
45. Paul SM, Purdy RH. Neuroactive steroids. FASEB J. 1992;6:2311-2322.
46. Besedovsky L, Lange T, Born J. Sleep and immune function. Pflugers Arch. 2012;463:121-137.
47. Popovic RM, White DP. Upper airway muscle activity in normal women: influence of hormonal status. J Appl Physiol. 1998;84:1055-1062.
48. Fauser BC, Laven JS, Tarlatzis BC, et al. Sex steroid hormones and reproductive disorders: impact on women's health. Reprod Sci. 2011;18:702-12.
49. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285):785-95.
50. Gielen E, Vanderschueren D, Callewaert F, Boonen S. Osteoporosis in men. Best Pract Res Clin Endocrinol Metab. 2011;25:321-335.
51. Finkelstein JS, Brockwell SE, Mehta V, et al. Bone mineral density changes during the menstrual cycle. J Clin Endocrinol Metab. 1992;75:1038-1043.
52. Weinstein SL, Dolan LA, Cheng JC, Danielsson A, Morcuende JA. Adolescent idiopathic scoliosis. Lancet. 2008;371:1527-1537.
53. Marya S, Tambe AD, Millner PA, Tsirikos AI. Adolescent idiopathic scoliosis : a review of aetiological theories of a multifactorial disease. Bone Joint J. 2022;104-B:915-921.
54. Cheng JC, Castelein RM, Chu WC, Danielsson AJ, Dobbs MB, Grivas TB, Gurnett CA, Luk KD, Moreau A, Newton PO, Stokes IA, Weinstein SL, Burwell RG. Adolescent idiopathic scoliosis. Nat Rev Dis Primers. 2015;1:15030.
55. Zhang L, Zhang Q, Zhang Y, Arthur M, Teo EC, Bíró I, Gu Y. The Effect of Concave-Side Intertransverse Ligament Laxity on the Stress of AIS Lumbar Spine Based on Finite Element Method. Bioengineering (Basel). 2022;9:724.
56. Blogowska A, Rzepka-Górska I, Krzyzanowska-Swiniarska B. Growth hormone, IGF-1, insulin, SHBG, and estradiol levels in girls before menarche. Arch Gynecol Obstet. 2003;268:293-6.
57. Zheng S, Zhou H, Gao B, Li Y, Liao Z, Zhou T, Lian C, Wu Z, Su D, Wang T, Su P, Xu C. Estrogen promotes the onset and development of idiopathic scoliosis via disproportionate endochondral ossification of the anterior and posterior column in a bipedal rat model. Exp Mol Med. 2018;50:1-11.
58. Almeida M, Laurent MR, Dubois V, Claessens F, O'Brien CA, Bouillon R, Vanderschueren D, Manolagas SC. Estrogens and Androgens in Skeletal Physiology and Pathophysiology. Physiol Rev. 2017;97:135-187.
59. Wang W, Hayami T, Kapila S. Female hormone receptors are differentially expressed in mouse fibrocartilages. Osteoarthritis Cartilage. 2009;17: 646-654.
60. Fernandez-Bermejo E, García-Jiménez MA, Fernandez-Palomeque C, Munuera L. Adolescent idiopathic scoliosis and joint laxity: a study with somatosensory evoked potentials. Spine 1993;18 (7):918-922.
61. MacNamara P, O'Shaughnessy C, Manduca P, Loughrey HC. Progesterone receptors are expressed in human osteoblast-like cell lines and in primary human osteoblast cultures. Calcif Tissue Int. 1995;57:436-41.
62. Payas A, Batin S, Kurtoğlu E, Arik M, Seber T, Uçar İ, Unur E. Is the Integration Problem in the Sensoriomotor System the Cause of Adolescent Idiopathic Scoliosis? J Pediatr Orthop. 2023;43: e111-e119.
63. Assaiante C, Mallau S, Viel S, Jover M, Schmitz C. Development of postural control in healthy children: a functional approach. Neural Plast. 2005;12:109-18; discussion 263-72.
64. Park Y, Ko JY, Jang JY, Lee S, Beom J, Ryu JS. Asymmetrical activation and asymmetrical weakness as two different mechanisms of adolescent idiopathic scoliosis. Sci Rep. 2021;11:17582.
65. Maurice T, Urani A, Phan VL, Romieu P. The interaction between neuroactive steroids and sigma1 receptor function: behavioral consequences and therapeutic opportunities. Brain Res Brain Res Rev. 2001;37:116-132.
66. Domenech J, García-Martí G, Martí-Bonmatí L, Barrios C, Tormos JM, Pascual-Leone A. Abnormal activation of the motor cortical network in idiopathic scoliosis demonstrated by functional MRI. Eur Spine J. 2011;20:1069-78.
67. Wu J, Qiu Y, Zhang L, et al. Association of estrogen receptor gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. Spine 2006;31:1131-1136.
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