Chris D. Meletis, N.D.
A scientific framework for restoring adrenal and gonadal hormone stability by supporting mitochondrial bioenergetics, antioxidant capability, and adaptogenic stress resilience—upstream of testosterone, cortisol, and thyroid therapies.
Summary
This text explores how mitochondrial operate underpins adrenal and gonadal steroidogenesis, contributing to hypogonadism, low libido, and adrenal insufficiency when impaired. It outlines evaluation methods and integrative therapies—together with mitochondrial vitamins, antioxidants, adaptogens, way of life, and thyroid help—to construct a resilient basis for long-term hormone optimization
There’s an age previous query, is it higher to provide a person a fish or educate him to fish? Nicely, the reply is complicated with regards to hormone optimization. As naturopathic physicians and purposeful drugs suppliers, we should assess the person physiological complexity, compliance, and dedication of the affected person to handle the underlying etiologies which have led to suboptimal adrenal or gonadal operate. The applying of the principal philosophy of treating the trigger, Tolle causam, is the perfect reply if the affected person can deal with full physique wellness.
Steadily, the trigger is an underrecognized issue equivalent to mitochondria dysfunction. Efficient administration of hypogonadism, low libido, or adrenal insufficiency requires cautious consideration of each mitochondrial energetics and adrenal operate, as these two methods type the biochemical basis of steroidogenesis.1 Knowledge point out mitochondrial dysfunction and adrenal dysregulation as main etiological components underlying declines in intercourse hormone synthesis.1,2
Supporting mitochondrial operate is paramount to addressing a affected person’s physiological resilience and capability to deal with anabolic and catabolic adrenal influences. As each hormonal pathways influence distal cells that should even have the mitochondrial capability within the type of ATP power to optimally reply to upregulation. Efficient mitochondrial capability additionally permits for a extra considerable hormonal presence, which impacts the 37 trillion cells that comprise the affected person sitting in entrance of us. Though this text is introduced together with this month’s male-health-themed choices, the identical applies for feminine hormonal stability and well being as effectively.
Mitochondrial Website of Steroidogenesis
Steroid hormones come up inside mitochondria by way of the conversion of ldl cholesterol to pregnenolone by cytochrome P450 side-chain cleavage enzyme (CYP11A1) situated on the internal mitochondrial membrane.3 Impaired electron transport or decreased mitochondrial membrane potential immediately limits steroid output.4 Correct operate of the StAR protein can be mandatory for ldl cholesterol import, and its deficiency ends in mixed adrenal and gonadal failure.5
Histologic research present that adrenal mitochondria are additionally linked to adrenal medulla operate. All too typically we fall into the development of treating and supporting the adrenal cortex, but the adrenal medulla can be by intention a part of adrenal responsiveness and wholesome physiology.6 CRF (corticotropin-releasing issue) will increase the spontaneous discharge fee of locus coeruleus (LC) neurons and enhances norepinephrine (NE) launch within the prefrontal cortex whereas glucocorticoids appear to exert extra inhibitory results on NE launch.7,8 Those self same neurotransmitters are launched from the adrenal medulla in occasions of stress. This is among the causes that sufferers expertise the “wired however drained” syndrome with decrease than wholesome physiological adrenal glucocorticoid manufacturing.
Illnesses producing variants of CYP11A1 or membrane fusion proteins equivalent to OPA1 typically manifest as each adrenal insufficiency and hypogonadism.6
Intercourse Hormone Regulation of Mitochondrial Biogenesis
Intercourse steroids reciprocally modulate mitochondrial biogenesis. Androgens activate peroxisome proliferator-activated receptor gamma co-activator (PGC-1α) transcription issue, stimulating mitochondrial DNA (mtDNA) replication.9,10 Research reveal restoration of mind mitochondrial operate following testosterone remedy in getting older males.11 Estrogens exert related protecting management on the mitochondria.12 I typically remind my older male sufferers with age-matched feminine companions that it’s not unusual to see a serum estradiol degree for males being equal or increased than their feminine counterpart if she is just not on hormone alternative.
Adrenal Cortex as a Mitochondria-Dense Organ
The adrenal cortex accommodates one of many highest mitochondrial densities of any endocrine tissue on account of its steroidogenic calls for.4,13 Adrenocortical mitochondria combine bioenergetics and steroid metabolism, and disruption of membrane potential or phospholipid transforming has been linked to glucocorticoid deficiency.13 Power stress triggers sustained activation of the hypothalamic–pituitary–adrenal axis, which preferentially directs ldl cholesterol towards cortisol synthesis.14 This persistent diversion, referred to as pregnenolone steal, underscores the vulnerability of steroidogenesis to mitochondrial exhaustion.
Mitochondrial Dysfunction in Endocrine Pathophysiology
Mitochondrial issues generally current with multisystem endocrine manifestations—adrenal insufficiency, hypogonadism, and thyroid secondary suppression—illustrate the common requirement of mitochondrial integrity for steroid biosynthesis.15 I make it some extent to teach my sufferers that hormones by their nature have broad and far-reaching results distally from the gland of origin. When supported with botanical, weight-reduction plan, way of life, nutraceuticals, or prescribed drugs, the focused tissues should even have enough mitochondrial operate to take up and make the most of the vitamins being therapeutically provided. In spite of everything, it takes power to regain and maintain homeostasis.
Medical Evaluation
Analysis of adrenal-mitochondrial integrity contains measuring serum pregnenolone and DHEA-S as indicators of steroidogenic reserve. Lactate-to-pyruvate ratios and urinary natural acids assist infer mitochondrial redox effectivity, whereas the DHEA/7-keto-DHEA ratio displays HPA oxidative exercise. Persistent low ratios can counsel mitochondrial over-oxidation and cortisol dominance. I routinely carry out serum pregnenolone, DHEA, and DHEA sulfate labs for sufferers to evaluate their upstream capability and reserve, and to search for potential “particular person” hurdles that make them needing scientific intervention. I additionally routinely embrace each urinary and salivary hormone testing as effectively.
Therapeutic Framework
Restoration of mitochondrial capability supplies the biochemical basis for endocrine restoration. Proof helps the next sequence of interventions:
- Bioenergetic repletion with coenzyme Q10 (CoQ10), acetyl-l-carnitine, riboflavin, nicotinamide riboside, α-lipoic acid, and creatine to revive oxidative phosphorylation.16
- Mitochondrial antioxidant remedy utilizing N-acetylcysteine, glycine, mitoquinol, or glutathione to stop ROS-induced enzyme inhibition.17,18
- Adrenal adaptogenic modulation by way of Rhodiola rosea and Withania somnifera can normalize cortisol rhythm.19-21 Typically as clinicians we’ve our tried and confirmed combos of adaptogenic botanicals that we’ve included into our scientific protocols. I routinely impart the philosophical tenet that “a penny saved is a penny earned.” Or put one other manner, that conservation of adrenal output with the usage of L-theanine may also help a affected person keep cool, calm, and picked up as a way to scale back the influence of stress on the mitochondria and hormones.
One other technique of adaptogenic modulation is to make use of proprietary blends equivalent to mixture of Magnolia officinalis and Phellodendron amurense that was proven in a 2013 article to assist with cortisol imbalance.22 After 4 weeks of supplementation, salivary cortisol publicity was considerably (p<0.05) decrease (−18%) within the Relora group in comparison with placebo. In comparison with placebo, the Relora group had considerably higher (p<0.05) temper state parameters, together with decrease indices of General Stress (−11%), Rigidity (−13%), Despair (−20%), Anger (−42%), Fatigue (−31%), and Confusion (−27%), and better indices of International Temper State (+11%) and Vigor (+18%).
- Embracing the idea of treating upstream through the use of hormone precursor alternative with physiological pregnenolone or DHEA with refinement of dosages utilizing pre and publish lab monitoring. In spite of everything, each pregnenolone and DHEA confer essential impartial helpful physiological results within the physique impartial of downstream hormones of testosterone, estrogen, or progesterone, which is the all-too-often main objective to be addressed in sufferers. But, our philosophical strategy is treating your complete physique and never simply looking for the short repair that was recommended by a affected person’s Google or AI search or podcast they lately watched. There’s a potential time for cookbook drugs, but it’s our years of coaching and holistic strategy that provides our sufferers that additional edge to thrive in distinction to easily surviving. We’re in our sufferers’ lives for the lengthy sport.
- Way of life and circadian restoration, as sleep deprivation and glycemic instability worsen mitochondrial well being.23,24 Testing for sleep apnea, addressing loud night breathing of mattress companions that may hold sufferers awake, controlling blue mild publicity, and many others. are all paramount.
The Thyroid-Adrenal-Mitochondrial Interdependence
Thyroid hormone (T3) acts as a grasp regulator of mitochondrial biogenesis.25 Hypothyroidism thus compounds mitochondrial insufficiency and produces biochemical patterns resembling adrenal fatigue.26 Additionally it is noteworthy that T3 hormone and T2 hormone have a stimulatory impact on mitochondrial operate:27 But another excuse to contemplate porcine-based thyroid alternative remedy. T2 hormone is just not a standardized strategy, however it’s provided together with the standardized T3 and T4 in commercially accessible thyroid alternative pharmaceutical choices.28,29
We should remind our sufferers that once we deal with hypothyroidism and produce thyroid laboratory indices throughout the regular vary, we’ve actually elevated their basal metabolic fee, which routinely alters metabolism of hormones, medicines clearance, digestion, and energetic demand together with adrenal reserve.
Conclusion
There’s an interaction between the mitochondria, steroid manufacturing, and adrenal well being. Supporting the well being of the mitochondria is crucial for wholesome testosterone ranges and adrenal operate. The mitochondria’s position in manufacturing of testosterone and different hormones is a little-considered facet of males’s well being, however one that may make a big distinction in therapy outcomes.
Chris D. Meletis, ND is an educator, worldwide creator, and lecturer. He has authored 18 books and greater than 200 scientific articles in outstanding journals and magazines. Dr Meletis served as Dean of Naturopathic Medication and CMO for 7 years at NUNM. He was lately awarded the NUNM Corridor of Fame award by OANP, in addition to the 2003 Doctor of the Yr by the AANP. Dr Meletis spearheaded the creation of 16 free pure drugs healthcare clinics in Portland, OR. Dr Meletis serves as an academic advisor for Fairhaven Well being, Berkeley Life, TruGen3, US BioTek, and TruNiagen. He has practiced in Beaverton, OR, since 1992.
References:
1. Papadopoulos V, Miller WL. Position of mitochondria in steroidogenesis. Finest Pract Res Clin Endocrinol Metab. 2012;26(6):771-790.
2. Melchinger P, Garcia BM. Mitochondria are midfield gamers in steroid synthesis. Int J Biochem Cell Biol. 2023;160:106431.
3. Miller WL. Steroid hormone synthesis in mitochondria. Mol Cell Endocrinol. 2013;379(1-2):62-73.
4. Vega-Vásquez T, Langgartner D, Wang JY, Reber SO, Picard M, Basualto-Alarcón C. Mitochondrial morphology within the mouse adrenal cortex: Affect of continual psychosocial stress. Psychoneuroendocrinology. 2024;160:106683.
5. Horikawa R. [Congenital lipoid adrenal hyperplasia]. Nihon Rinsho. 2004;62(2):351-356.
6. Neuhaus JF, Baris OR, Kittelmann A, Becker Ok, Rothschild MA, Wiesner RJ. Catecholamine Metabolism Induces Mitochondrial DNA Deletions and Results in Extreme Adrenal Degeneration throughout Growing older. Neuroendocrinology. 2017;104(1):72-84.
7. Valentino RJ, Foote SL, Web page ME. The locus coeruleus as a website for integrating corticotropin-releasing issue and noradrenergic mediation of stress responses. Ann N Y Acad Sci. 1993;697:173-188.
8. Smagin GN, Swiergiel AH, Dunn AJ. Corticotropin-releasing issue administered into the locus coeruleus, however not the parabrachial nucleus, stimulates norepinephrine launch within the prefrontal cortex. Mind Res Bull. 1995;36(1):71-76.
9. Ventura-Clapier R, Garnier A, Veksler V. Transcriptional management of mitochondrial biogenesis: the central position of PGC-1alpha. Cardiovasc Res. 2008;79(2):208-217.
10. Gharahdaghi N, Rudrappa S, Brook MS, et al. Testosterone remedy induces molecular programming augmenting physiological variations to resistance train in older males. J Cachexia Sarcopenia Muscle. 2019;10(6):1276-1294.
11. Yan W, Zhang T, Kang Y, et al. Testosterone ameliorates age-related mind mitochondrial dysfunction. Growing older (Albany NY). 2021;13(12):16229-16247.
12. Malik S, Chakraborty D, Agnihotri P, et al. Mitochondrial proteomics reveals the influence of Estrogen in enhancing power metabolism of patient-derived fibroblast-like synoviocytes in rheumatoid arthritis. Inflamm Res. 2025;74(1):146.
13. Jefcoate C. Excessive-flux mitochondrial ldl cholesterol trafficking, a specialised operate of the adrenal cortex. J Clin Make investments. 2002;110(7):881-890.
14. Lauren Thau JG, Sandeep Sharma. Physiology, Cortisol. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK538239/. Revealed 2023. Accessed October 24, 2025.
15. Duarte A, Poderoso C, Cooke M, et al. Mitochondrial fusion is crucial for steroid biosynthesis. PLoS One. 2012;7(9):e45829.
16. Dietary Dietary supplements for Major Mitochondrial Issues: Reality Sheet for Well being Professionals. Nationwide Institutes of Well being. https://ods.od.nih.gov/factsheets/PrimaryMitochondrialDisorders-HealthProfessional/. Revealed 2020. Accessed October 24, 2025.
17. Kumar P, Liu C, Suliburk J, et al. Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Irritation, Bodily Perform, and Growing older Hallmarks: A Randomized Medical Trial. J Gerontol A Biol Sci Med Sci. 2023;78(1):75-89.
18. Abdeahad H, Moreno DG, Bloom SI, Norman L, Lesniewski LA, Donato AJ. MitoQ reduces senescence burden in doxorubicin-treated endothelial cells by lowering mitochondrial ROS and DNA injury. Am J Physiol Coronary heart Circ Physiol. 2025;329(5):H1154-h1161.
19. Panossian A, Wikman G. Proof-based efficacy of adaptogens in fatigue, and molecular mechanisms associated to their stress-protective exercise. Curr Clin Pharmacol. 2009;4(3):198-219.
20. Olsson EM, von Schéele B, Panossian AG. A randomised, double-blind, placebo-controlled, parallel-group examine of the standardised extract shr-5 of the roots of Rhodiola rosea within the therapy of topics with stress-related fatigue. Planta Med. 2009;75(2):105-112.
21. Lopresti AL, Smith SJ, Malvi H, Kodgule R. An investigation into the stress-relieving and pharmacological actions of an ashwagandha (Withania somnifera) extract: A randomized, double-blind, placebo-controlled examine. Medication (Baltimore). 2019;98(37):e17186.
22. Talbott SM, Talbott JA, Pugh M. Impact of Magnolia officinalis and Phellodendron amurense (Relora®) on cortisol and psychological temper state in reasonably careworn topics. J Int Soc Sports activities Nutr. 2013;10(1):37.
23. Dassanayaka S, Readnower RD, Salabei JK, et al. Excessive glucose induces mitochondrial dysfunction independently of protein O-GlcNAcylation. Biochem J. 2015;467(1):115-126.
24. Luo Z, Ji R, Ye R, Shi Y, Pang Q, Yin M. Lowered serum ranges of mitochondria-derived peptide MOTS-c in sufferers with obstructive sleep apnea. Sleep Biol Rhythms. 2025;23(3):305-311.
25. Anthonsen S, Larsen J, Pedersen PL, Dalgaard LT, Kvetny J. Basal and T₃-induced ROS manufacturing in lymphocyte mitochondria is elevated in kind 2 diabetic sufferers. Horm Metab Res. 2013;45(4):261-266.
26. Romão JS, Neto JGO, Andrade CBV, Carvalho JJ, Pazos-Moura CC, Oliveira KJ. Hypothyroidism modulates mitochondrial dynamics and mitophagy within the coronary heart of rats below fed and fasting situations. Life Sci. 2024;359:123254.
27. Goglia F, Moreno M, Lanni A. Motion of thyroid hormones on the mobile degree: the mitochondrial goal. FEBS Lett. 1999;452(3):115-120.
28. Zucchi R, Rutigliano G, Saponaro F. Novel thyroid hormones. Endocrine. 2019;66(1):95-104.
29. Maria Moreno M, Giacco A, Di Munno Celia Goglia F. Molecular and Mobile Endocrinology. 2017;458(15):121-126