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The first article in this series reviewed the metabolism and cognitive and behavioral effects of neuroactive steroids. The second article reviewed the observed side effects of finasteride and the biomarkers of post-finasteride patients with persistent symptomology. In this article, I will briefly speculate on how one could attenuate some of the deleterious effects of finasteride. Note that much of what is discussed here is also applicable to people interested in improving brain function broadly.
REVIEWING THE EVIDENCE
Though they have not been measured in the CSF of active finasteride users, it is certain that finasteride acutely lowers levels of the steroids THDOC, allopregnanolone, androstanediol, and androsterone. Recall that allopregnanolone and THDOC are the most potent neurosteroids. While allopregnanolone and its precursor progesterone were both lowered across all three examined CSF studies, it is interesting to note that androsterone, testosterone, and DHEA were frequently raised, though DHT was lowered. It appears that discontinued chronic use produces a different phenotype than acute use, likely due to the body’s attempt to establish homeostasis.
BUILDING A STRATEGY
Broadly, our approach can either be hormonal or not. Hormonally, we have three options. First, we can try to increase the natural hormones that finasteride therapy diminishes. Second, we can use synthetic progestogens to produce similar outcomes. Third, we can increase other endogenous steroids, or use their synthetic analogues or receptor modulators. Outside of hormones, we can build a program to attempt to replicate the protective roles of neurosteroids on myelination, neuroinflammation, neuronal apoptosis, anxiolysis, mood, and memory through other mechanisms. As a non-hormonal approach is out of the scope of this series, and a discussion of all hormone therapies will exhaust the reader, we will mostly restrict our discussion to hormonal approaches with progestogens.
ALLOPREGNANOLONE
Of the missing neurosteroids, the lowest hanging fruit is allopregnanolone. THDOC appears equally powerful, but it is less understood, while androstanediol and androsterone are weaker and do not appear lowered in post-finasteride patients, implying an easier recovery.
The problem with allopregnanolone is its short half-life[1], low bio-availability limiting oral administration (because of quick elimination by glucuronide or sulfate conjugation)[2], development of a tolerance due to its GABAergic and dopaminergic activity[3], and addiction potential[4]. Despite these concerns, allopregnanolone is the only FDA-approved treatment for postpartum depression[5], where it is delivered via continuous IV for days.
Due to these issues, allopregnanolone cannot be conveniently supplemented directly. It would appear that a combination of increasing progesterone and using an SSRI would provide the greatest, stable, and tolerable allopregnanolone increase while under finasteride treatment.
PROGESTERONE
Although we have focused our discussion around 5AR-dependent neurosteroids, the reader will recall the profound neuroactive profile of progesterone from the first article in this series. Progesterone supplementation will produce a dual effect from progesterone itself as well as its downstream metabolites, including allopregnanolone, although 5AR inhibition will reduce the rate at which allopregnanolone is formed.
Unfortunately, one cannot rely on regular American ‘mini pill’ contraceptives, as these are not progesterone but particularly undesirable synthetic progestins. Progesterone is not very bioavailable after oral consumption, and the American market decided to take the synthetic route, instead of improving upon the natural steroid.
Thankfully, some European nations were of a different mind. France is particularly known for using micronized progesterone as a contraceptive, as the micronized version is better absorbed[6]. Still, it can be improved upon further for our uses. Intranasal[7][8] administration will preferentially increase cerebral availability[9] of progesterone. Moreover, it will also increase the rate of conversion to allopregnanolone while under finasteride treatment, because more of the pregnanolone will be available for type 1 isoform 5AR conversion. Recall that type 1 is the only 5AR isoform yet identified in the brain, and it is the isoform least inhibited by finasteride. (Note that a recipe to prepare progesterone nasal spray is in this paper, while this paper used a less mimicable proprietary oleogel).
Though intranasal administration of progesterone has already been used to protect mouse brains from ischemic stroke[10], there are two concerns. First, there is a risk of an addictive effect due to the acute dopaminergic response[11] produced by intranasal delivery of progesterone. Second, there is a concern for withdrawal due to the enhanced expression of the GABAA receptor a4 subunit[12] that comes with pharmacologic dosing of progesterone. Nonetheless, if progesterone is lowered as much as observed in the CSF studies, a lower dose used intermittently may neither produce a super-physiologic level of progesterone nor a withdrawal.
RAISING PROGESTOGENS BY OTHER MEANS
The astute reader will recall from the first article in this series that the rate-limiting step in the brain’s synthesis of steroids is the translocator protein 18 kDa (TSPO). Consequently, TSPO has recently become the focus of a flurry of research papers, all seeking to develop well-tolerated ligands that activate TSPO, thereby increasing cholesterol supply to P450scc at the inner mitochondrial membrane and leading to more brain synthesis of steroids. Endogenous ligands include the diazepam binding receptor (DBI), triakontatetraneuropeptide (TTN), phospholipase A2 (PLA2), and protoporphyrin IX[13]. TSPO ligands are under study as a therapeutic measure for Alzheimer’s patients and for neurotrauma[14], as a replacement for benzodiazepines for the treatment of anxiety[15] because of their favorable side effect profile[16], and for their antidepressant effects[17]. While increasing hormone synthesis in the brain more broadly is attractive, synthetic analogues of individual hormones also offer advantages.
Because of allopregnanolone’s quick metabolism and great therapeutic potential, synthetic analogues have been in development for some time. One allopregnanolone analogue, BR 297, exhibits superior neuroprotective qualities to allopregnanolone[18][19]. Allopregnanolone’s 3b-methyl analogue, ganaxolone[20], is being studied in human trials for the treatment of epilepsy[21]. Although the drug is metabolized quickly, requiring thrice-a-day administration[22], it does not have the potential to undergo oxidation to the ketone, which would restore activity at hormone receptors, as happens to allopregnanolone. Brexanolone, brand name Zulresso, is an allopregnanolone analogue FDA-approved for the treatment of postpartum depression[23]. Note that not all synthetic analogues of allopregnanolone are safe. Alphaxalone has been shown to be neurotoxic[24].
While synthetic progestins can be used to agonize the progesterone receptor, they do not convert into the powerful neuroprotective derivatives like allopregnanolone that have complex and still not fully understood effects. Moreover, while synthetic progestins have been associated with breast cancer[25] and thrombotic[26] risk, progesterone has not been. Nonetheless, we have discussed the synthetic progestin segesterone acetate (brand name Nestorone), which has exhibited a remarkable ability for myelination akin to progesterone[27], is neuroprotective[28], and promotes neurogenesis and brain plasticity[29]. Note that not all synthetic progestins have this ability, others, such as medroxyprogesterone acetate (MPA), cannot enhance myelination and may be dangerous. There are also selective progesterone receptor modulators (SPRMs), but their neural effects have yet to be evaluated, as research with SPRMs is currently focused on the subject of uterine fibroids[30].
Beware that synthetic steroids can have unintended consequences. RU486, an analogue of allopregnanolone, unintendedly affects the enzyme 3b-hydroxysteroid which converts pregnenolone to progesterone, and the enzymes 21-hydroxylase and 11-hydroxylase in rat adrenals[31], while it inhibits aromatase and 17-hydroxylase activity in rat gonads[32].
OTHER STEROIDS
The most powerful neuroactive hormone of all is estrogen. Progesterone only exceeds estrogen’s neuroprotective power in the study of traumatic brain injury. Though a discussion of estrogen is out of the scope of this series, I want the reader to remember that estrogen potentiates progesterone’s neuroactive effects and to be aware that estrogen is even more powerful for cognitive performance and well-being than progesterone. Estrogen can be increased by increasing production of gonadotropin releasing hormone with human chorionic gonadotropin, by supplementing its upstream hormones, like DHEA, pregnenolone, or testosterone, or by increasing the activity of aromatase. There are also powerful and well-studied selective estrogen receptor modulators[33][34] with widespread health benefits as well as enticing synthetic estrogen analogues, such the mirror image of estradiol, ent-17b-estradiol, which also exerts neuroprotective actions without producing traditionally estrogenic effects[35].
Even before their conversion, DHEA, DHEA sulfate, pregnenolone, and pregnenolone sulfate have potent neuroactive effects, though, as we have seen, some of them are excitatory and they can sometimes increase the effect of neurotoxic events. There are synthetic analogues of these molecules also. The synthetic steroid 5a-androst-3b,5,6b-triol was developed from DHEA and has been found to have a dose-dependent neuroprotective effect in animal models of hypoxic ischemia. It preserved neuron integrity, prevented mitochondrial membrane degradation, preserved ATP production, and reduced oxidative stress[36]. It also reduces neuroinflammation, decreasing TNF-a expression and preventing NF-kB activation[37]. There is evidence indicating that molecules with a 3b,5a,6b-trihydroxy sterol structure may exhibit even greater neuroprotective effects[38].
CONCLUSION
Neuroactive steroids contribute greatly to our well-being. Finasteride’s growingly notorious reputation is a testament not to the value of DHT, but to the value of progesterone and allopregnanolone. It is unfortunate that instead of producing progesterone/pregnenolone combination nasal sprays, or transdermal generic segesterone acetate, or the allopregnanolone analogue BR 297, ‘research chemical’ websites spend their efforts on racetams, copper peptides, and MK677. The only way to change this misallocation of resources is to educate the biohacking/nootropics community, so I hope that you will spread this series of articles around, and if not, then tell people what you learned about neurosteroids.
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[1] Timby, E., Balgård, M., Nyberg, S., Spigset, O., Andersson, A., Porankiewicz-Asplund, J., ... & Poromaa, I. S. (2006). Pharmacokinetic and behavioral effects of allopregnanolone in healthy women. Psychopharmacology, 186(3), 414. [2] Irwin, R. W., Solinsky, C. M., & Brinton, R. D. (2014). Frontiers in therapeutic development of allopregnanolone for Alzheimer’s disease and other neurological disorders. Frontiers in cellular neuroscience, 8, 203. [3] Zhu, D., Birzniece, V., Bäckström, T., & Wahlström, G. (2004). Dynamic aspects of acute tolerance to allopregnanolone evaluated using anaesthesia threshold in male rats. British journal of anaesthesia, 93(4), 560-567. [4] Grant, K. A., Helms, C. M., Rogers, L. S., & Purdy, R. H. (2008). Neuroactive steroid stereospecificity of ethanol-like discriminative stimulus effects in monkeys. Journal of Pharmacology and Experimental Therapeutics, 326(1), 354-361. [5] Walton, N., & Maguire, J. (2019). Allopregnanolone-based treatments for postpartum depression: Why/how do they work?. Neurobiology of stress, 11, 100198. [6] de Lignières, B. (1999). Oral micronized progesterone. Clinical therapeutics, 21(1), 41-60. [7] Costantino, H. R., Illum, L., Brandt, G., Johnson, P. H., & Quay, S. C. (2007). Intranasal delivery: physicochemical and therapeutic aspects. International journal of pharmaceutics, 337(1-2), 1-24. [8] Chauhan, M. B., & Chauhan, N. B. (2015). Brain uptake of neurotherapeutics after intranasal versus intraperitoneal delivery in mice. Journal of neurology and neurosurgery, 2(1). [9] Ducharme, N., Banks, W. A., Morley, J. E., Robinson, S. M., Niehoff, M. L., & Mattern, C. (2010). Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration. European journal of pharmacology, 641(2-3), 128-134. [10] Fréchou, M., Zhu, X., Liere, P., Pianos, A., Schumacher, M., Mattern, C., & Guennoun, R. (2020). Dose-dependent and long-term cerebroprotective effects of intranasal delivery of progesterone after ischemic stroke in male mice. Neuropharmacology, 108038. [11] de Souza Silva, M. A., Topic, B., Huston, J. P., & Mattern, C. (2008). Intranasal administration of progesterone increases dopaminergic activity in amygdala and neostriatum of male rats. Neuroscience, 157(1), 196-203. [12] Smith, S. S., Gong, Q. H., Hsu, F. C., Markowitz, R. S., & Li, X. (1998). GABA A receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature, 392(6679), 926-929. [13] Rupprecht, R., Papadopoulos, V., Rammes, G., Baghai, T. C., Fan, J., Akula, N., ... & Schumacher, M. (2010). Translocator protein (18 kDa)(TSPO) as a therapeutic target for neurological and psychiatric disorders. Nature reviews Drug discovery, 9(12), 971. [14] Papadopoulos, V., & Lecanu, L. (2009). Translocator protein (18 kDa) TSPO: an emerging therapeutic target in neurotrauma. Experimental neurology, 219(1), 53-57. [15] Rupprecht, R., Rammes, G., Eser, D., Baghai, T. C., Schüle, C., Nothdurfter, C., ... & Uzunov, V. (2009). Translocator protein (18 kD) as target for anxiolytics without benzodiazepine-like side effects. Science, 325(5939), 490-493. [16] Nothdurfter, C., Rammes, G., Baghai, T. C., Schüle, C., Schumacher, M., Papadopoulos, V., & Rupprecht, R. (2012). Translocator protein (18 kDa) as a target for novel anxiolytics with a favourable side‐effect profile. Journal of neuroendocrinology, 24(1), 82-92. [17] Ren, P., Ma, L., Wang, J. Y., Guo, H., Sun, L., Gao, M. L., ... & Guo, W. Z. (2020). Anxiolytic and Anti‑depressive Like Effects of Translocator Protein (18 kDa) Ligand YL‑IPA08 in a Rat Model of Postpartum Depression. Neurochemical research. [18] Lejri, I., Grimm, A., Miesch, M., Geoffroy, P., Eckert, A., & Mensah-Nyagan, A. G. (2017). Allopregnanolone and its analog BR 297 rescue neuronal cells from oxidative stress-induced death through bioenergetic improvement. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1863(3), 631-642. [19] Taleb, O., Patte‐Mensah, C., Meyer, L., Kemmel, V., Geoffroy, P., Miesch, M., & Mensah‐Nyagan, A. G. (2018). Evidence for effective structure‐based neuromodulatory effects of new analogues of neurosteroid allopregnanolone. Journal of neuroendocrinology, 30(2), e12568. [20] Nohria, V., & Giller, E. (2007). Ganaxolone. Neurotherapeutics, 4(1), 102-105. [21] Carter, R. B., Wood, P. L., Wieland, S., Hawkinson, J. E., Belelli, D., Lambert, J. J., ... & Bolger, M. B. (1997). Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3α-hydroxy-3β-methyl-5α-pregnan-20-one), a selective, high-affinity, steroid modulator of the γ-aminobutyric acidA receptor. Journal of Pharmacology and Experimental Therapeutics, 280(3), 1284-1295. [22] Monaghan, E. P., McAuley, J. W., & Data, J. L. (1999). Ganaxolone: a novel positive allosteric modulator of the GABAA receptor complex for the treatment of epilepsy. Expert opinion on investigational drugs, 8(10), 1663-1671. [23] Walton, N., & Maguire, J. (2019). Allopregnanolone-based treatments for postpartum depression: Why/how do they work?. Neurobiology of stress, 11, 100198. [24] Tesic, V., Joksimovic, S. M., Quillinan, N., Krishnan, K., Covey, D. F., Todorovic, S. M., & Jevtovic-Todorovic, V. (2020). Neuroactive steroids alphaxalone and CDNC24 are effective hypnotics and potentiators of GABAA currents, but are not neurotoxic to the developing rat brain. British journal of anaesthesia. [25] Fournier, A., Berrino, F., & Clavel-Chapelon, F. (2008). Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast cancer research and treatment, 107(1), 103-111. [26] Canonico, M., Fournier, A., Carcaillon, L., Olié, V., Plu-Bureau, G., Oger, E., ... & Scarabin, P. Y. (2010). Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study. Arteriosclerosis, thrombosis, and vascular biology, 30(2), 340-345. [27] Hussain, R., El-Etr, M., Gaci, O., Rakotomamonjy, J., Macklin, W. B., Kumar, N., ... & Ghoumari, A. M. (2011). Progesterone and Nestorone facilitate axon remyelination: a role for progesterone receptors. Endocrinology, 152(10), 3820-3831. [28] Tanaka, M., Ogaeri, T., Samsonov, M., & Sokabe, M. (2019). Nestorone exerts long-term neuroprotective effects against transient focal cerebral ischemia in adult male rats. Brain research, 1719, 288-296. [29] Chen, S., Kumar, N., Mao, Z., Sitruk-Ware, R., & Brinton, R. D. (2018). Therapeutic progestin segesterone acetate promotes neurogenesis: implications for sustaining regeneration in female brain. Menopause, 25(10), 1138-1151. [30] Bouchard, P., Chabbert-Buffet, N., & Fauser, B. C. (2011). Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety. Fertility and sterility, 96(5), 1175-1189. [31] Albertson, B. D., Hill, R. B., Sprague, K. A., Wood, K. E., Nieman, L. K., & Loriaux, D. L. (1994). Effect of the antiglucocorticoid RU486 on adrenal steroidogenic enzyme activity and steroidogenesis. European journal of endocrinology, 130(2), 195-200. [32] Sanchez, P. E., Ryan, M. A., Kridelka, F., Gielen, I., Ren, S. G., Albertson, B., ... & Cassorla, F. (1989). RU-486 inhibits rat gonadal steroidogenesis. Hormone and metabolic research, 21(07), 369-371. [33] Cordey, M., Gundimeda, U., Gopalakrishna, R., & Pike, C. J. (2005). The synthetic estrogen 4-estren-3α, 17β-diol (estren) induces estrogen-like neuroprotection. Neurobiology of disease, 19(1-2), 331-339. [34] Covey, D. F. (2009). ent-Steroids: novel tools for studies of signaling pathways. Steroids, 74(7), 577-585. [35] Green, P. S., Yang, S. H., Nilsson, K. R., Kumar, A. S., Covey, D. F., & Simpkins, J. W. (2001). The nonfeminizing enantiomer of 17β-estradiol exerts protective effects in neuronal cultures and a rat model of cerebral ischemia. Endocrinology, 142(1), 400-406. [36] Chen, J., Leng, T., Chen, W., Yan, M., Yin, W., Huang, Y., ... & Zhang, J. (2013). A synthetic steroid 5α-androst-3β, 5, 6β-triol blocks hypoxia/reoxygenation-induced neuronal injuries via protection of mitochondrial function. Steroids, 78(10), 996-1002. [37] Yan, M., Leng, T., Tang, L., Zheng, X., Lu, B., Li, Y., ... & Yin, W. (2017). Neuroprotectant androst-3β, 5α, 6β-triol suppresses TNF-α-induced endothelial adhesion molecules expression and neutrophil adhesion to endothelial cells by attenuation of CYLD-NF-κB pathway. Biochemical and biophysical research communications, 483(2), 892-896. [38] Li, X., Chen, X., Chen, J., Zhou, S., Wen, J., Huang, Y., ... & Zhang, J. (2015). Synthesis and neuroprotection of 5α-androst-3β, 5, 6β-triol derivatives. Ther. Targets Neurol. Dis, 2, e831.
