NMN and Hormones: How Does NAD+ Affect Estrogen, Testosterone, Melatonin, and Thyroid Hormone?

Aging is a physiological process that brings about various changes within our bodies. Among these changes, alterations in hormone levels play a critical role in the aging process and its impact on our health. The hormonal changes observed with aging affect energy levels, cognitive health, and sleep quality as well as longevity and healthspan. In this article, we review the relationship between aging, hormones, and health, shedding light on the potential role of Nicotinamide Mononucleotide (NMN) in supporting hormone health. 

What Are Hormones? 

Hormones are chemical messengers that regulate a wide range of bodily functions, including muscle growth, energy, metabolism, mood, and reproduction. As time progresses, our bodies experience notable alterations in hormone levels, which affects women and men differently.  

Hormonal Changes Specific to Women 

In the context of women's aging, estrogen and progesterone stand out as two hormones where changes in levels have significant effects on longevity and healthspan. Estrogen, recognized as a pivotal female hormone, experiences natural fluctuations throughout different age ranges. During reproductive years, estrogen levels peak, regulating the menstrual cycle and reproductive health. As women age, their estrogen levels begin to decline steadily (1). 

This decline in estrogen production signifies the onset of perimenopause and menopause. Additionally, the diminishing levels of estrogen bring about changes in menstrual patterns, eventually leading to the cessation of menstruation. This transition into menopause is often accompanied by a variety of undesirable symptoms, including hot flashes, night sweats, mood fluctuations, and a decrease in bone density (2). Research shows that women are more likely to suffer from a decline in bone density, increasing risk for injury and reduced heathspan (3). This increased risk is in part due to the decline of estrogen levels. 

Along with estrogen, progesterone also exhibits age-related fluctuations in women. Progesterone plays a crucial role in the menstrual cycle by preparing the uterine lining for potential pregnancy. Throughout the fertile years, progesterone levels undergo cyclic variations, aligning with the phases of the menstrual cycle. However, as women approach perimenopause and menopause, progesterone levels often decrease, resulting in shifts in menstrual patterns (4). This decline can contribute to irregular menstrual cycles and may be accompanied by symptoms such as sleep disturbances and mood swings. 

Hormonal Changes Specific to Men 

While much attention is focused on women's hormonal changes during aging, it’s equally important to assess how aging impacts hormone levels in men. Testosterone, the primary male hormone, is a hormone that plays a critical role in promoting energy, vitality, performance, and strength. Between the ages of 35-40, testosterone production begins to decline, with a 1-3% decrease in testosterone observed annually (5). 

This decline can manifest as changes in body composition, including a decrease in muscle mass and an increase in body fat. Maintaining muscle mass into your older years is critical to promote longevity and improve quality of life, shedding light on the importance of maintaining healthy testosterone levels as you age. In addition to a reduction in muscle mass, low testosterone levels can also influence energy levels, libido, sleep patterns, and cognitive function. 

NAD+ and Hormone Regulation 

While there are a variety of factors that impact hormone regulation, one key molecule that has a significant impact is Nicotinamide Adenine Dinucleotide, or NAD+. NAD+ is a coenzyme that plays critical roles in various cellular processes, including energy production and DNA repair. NAD+ levels naturally decline with age, resulting in an estimated 50% reduction in NAD+ levels by age 50 (6). Researchers believe this decline in NAD+ is a key contributor to cellular aging. Animal studies have shown that increasing NAD+ levels extends lifespan (7). Age-related declines in NAD+ levels are closely associated with changes in hormone levels.  

In the following section, we will discuss how NAD+ levels influence hormone regulation, the consequences of declining NAD+ with age on hormones, and the potential benefits of maintaining healthy NAD+ levels in addressing age-related hormonal issues. 

NAD+ and Sirtuins

Often overlooked as it relates to hormone regulation, a group of proteins known as sirtuins are critical for fine-tuning of hormone sensitivity. These sirtuins, when activated, play a critical role in modulating the responsiveness of hormone receptors. For example, sirtuins can enhance the sensitivity of estrogen receptors (8). When sirtuins are activated, estrogen receptors are more receptive to the estrogen being produced by the body, meaning that estrogen can be utilized to perform its critical functions. This heightened sensitivity can be particularly important for regulating the menstrual cycle, maintaining bone density, and influencing mood.  

Additionally, sirtuins also play a role in influencing androgen receptor sensitivity (9). By supporting androgen receptor responsiveness, sirtuins can impact the body's ability to respond to testosterone. This affects muscle mass, bone density, and overall vitality in men. 

It is important to note that NAD+ acts as the essential activator of sirtuins. Since sirtuins cannot carry out their roles effectively without an adequate supply of NAD+ it is critical to maintain healthy NAD+ levels to support sirtuin-dependant hormone functions during aging. 

NAD+ and Estrogen

An additional way NAD+ is related to estrogen levels is through its intricate relationship with the enzyme 17β-Hydroxysteroid Dehydrogenase. This enzyme is important for the metabolism of estrogen, playing a pivotal role in the conversion of estrone to estradiol, the biologically active form of estrogen. Importantly, NAD+ serves as a coenzyme for 17β-Hydroxysteroid Dehydrogenase, actively participating in the chemical reactions that enable this conversion (10). 

When NAD+ levels are sufficient, they provide the necessary support for 17β-Hydroxysteroid Dehydrogenase to efficiently convert estrone into estradiol. This results in balanced estrogen levels, crucial for various bodily functions. However, if NAD+ levels decline, the enzymatic activity of 17β-Hydroxysteroid Dehydrogenase may be diminished, leading to a less efficient conversion process. As a result, estrogen levels may become imbalanced, with potential effects on healthspan and quality of life. 

NAD+ and Testosterone

NAD+ plays a critical role in testosterone synthesis by actively supporting the activity of a key enzyme called 3β-Hydroxysteroid Dehydrogenase (11). This enzyme is required for the biosynthesis of all classes of steroid hormones, including testosterone (12). In essence, 3β-Hydroxysteroid Dehydrogenase is a key player in the transformation of precursor molecules into testosterone. 

With sufficient NAD+ levels, this enzyme can efficiently carry out its role, ensuring that precursor molecules are effectively converted into testosterone. However, when NAD+ levels decline, the enzymatic reactions catalyzed by 3β-Hydroxysteroid Dehydrogenase may become less efficient. This can lead to a slowdown in the testosterone production process, potentially impacting overall testosterone levels. Reduced testosterone levels are associated with various symptoms of age-related health decline, including a decrease in muscle mass, lower bone density, and potential effects on overall quality of life (13). 

NAD+ and the Thyroid

NAD+ may play several roles in maintaining the proper functioning of the thyroid gland and the conversion of T4 to the more active T3 hormone. Enzymes involved in thyroid hormone synthesis, such as thyroid peroxidase (TPO), rely on NAD+ as a coenzyme for their proper function. Additionally, the conversion of T4 to T3, a critical step in thyroid hormone function, is facilitated by enzymes like type 2 deiodinase (D2), which are NAD+-dependent.  

While this connection isn’t fully understood, SIRT-1 activation has been shown to exhibit regulatory effects on thyroid hormones, which may be the link between NAD+ and thyroid hormone balance (13). The availability of NAD+ is crucial for maintaining the balance of T3 and T4 levels in the body due to NAD+ being required for sirtuin activation. Adequate NAD+ levels also support the proper functioning of thyroid enzymes, ensuring the synthesis and conversion of thyroid hormones occur efficiently. When NAD+ levels decline, the activity of these enzymes may be compromised, potentially leading to imbalances in thyroid hormone levels. Maintaining healthy NAD+ levels is essential for supporting thyroid health and overall metabolic function, as disruptions in NAD+ balance may lead to disruptions in metabolic processes of the thyroid.  

NAD+ and Melatonin

The connection between NAD+ and melatonin, often referred to as the "sleep hormone," is vital for regulating circadian rhythms and promoting sound sleep. Melatonin synchronizes the body's internal clock, and NAD+ influences its synthesis by activating key enzymes in the process. 

Specifically, NAD+ supports the activity of serotonin N-acetyltransferase (SNAT), a pivotal enzyme involved in melatonin production. SNAT converts serotonin into N-acetylserotonin, a precursor to melatonin (14). Adequate NAD+ levels ensure SNAT functions efficiently, regulating melatonin synthesis according to the body's circadian rhythm. 

Maintaining healthy NAD+ levels is essential for supporting the optimal synthesis of melatonin, which, in turn, contributes to a stable circadian rhythm and improved sleep patterns. The decline in NAD+ levels that can occur with aging or due to unhealthy lifestyle factors may affect melatonin production, potentially leading to sleep disturbances and disruptions in the sleep-wake cycle (15). Therefore, sustaining adequate NAD+ levels is crucial for promoting restful sleep and maintaining a healthy circadian rhythm. 

NMN for Hormone Support? 

Nicotinamide Mononucleotide (NMN) is a supplement that has gained popularity due to its potential to promote longevity and enhanced healthspan. While much of the research on NMN has focused on its longevity or performance related effects, an underexplored benefit of NMN lies in its potential influence hormone function. While we've extensively covered the benefits of NMN supplements in previous articles (you can find them here), let’s revisit the basics of NMN and how it may support hormone health. 

A key benefit of NMN is its ability to raise NAD+ levels in the body. Research has shown that Uthever NMN, found in all our NMN products, can boost NAD+ levels by up to 38% within just 60 days (15). While research has confirmed the benefits of increased NAD+ levels in animal studies, the specific effects of NMN on human hormone health are an area that hasn’t been thoroughly investigated. 

However, the ability of NMN to increase NAD+ levels suggests potential support for various hormone functions that rely on NAD+ for optimal performance. For example, initial studies have shown that NMN supports a variety of hormone-related processes including supporting healthy sleep quality.  

A 2022 study published in the Nutrients journal found that supplementing withjust 250 mg of NMN daily has positive effects on sleep quality (16). Additionally, NMN has been shown to restore fertility in aged animals by improving oocyte quality.17 Oocytes are immature egg cells that eventually mature and become an egg. A decline in oocyte quality is observed during menopause and is responsible for the decreased fertility associated with aging.  

Although extensive human studies are still in their early stages, these initial findings point toward NMN's promising role in promoting the well-being of hormone systems closely connected to the NAD+ pathway. As we await further research, it's reasonable to consider NMN's potential benefits for hormone function with cautious optimism, guided by the evolving scientific landscape in this area. 

Customer Anecdotes 

When consulting with customers on our Longevity Health Pro chat, I have found that NMN seems to have a significant impact on hormone levels. Several customers have shared their experiences with me, stating that they have seen alterations in lab markers such as an increase in testosterone for men and an increase of estrogen in women, which was accompanied by a reduction of menopause symptoms since beginning NMN. These anecdotes shed light on the potential effect of NMN in supporting healthy hormone levels with aging and NMN’s ability to promote improved healthspan during aging.  

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References:

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2. Santoro N, Roeca C, Peters BA, Neal-Perry G. The Menopause Transition: Signs, Symptoms, and Management Options. J Clin Endocrinol Metab. 2021;106(1):1-15. doi:10.1210/clinem/dgaa764 
3. McPhee C, Aninye IO, Horan L. Recommendations for Improving Women's Bone Health Throughout the Lifespan. J Womens Health (Larchmt). 2022;31(12):1671-1676. doi:10.1089/jwh.2022.0361 
4. Cable JK, Grider MH. Physiology, Progesterone. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558960/ 
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6. McReynolds MR, Chellappa K, Baur JA. Age-related NAD+ decline [published online ahead of print, 2020 Feb 22]. Exp Gerontol. 2020;134:110888. doi:10.1016/j.exger.2020.110888 
7. Fang EF, Lautrup S, Hou Y, et al. NAD+ in Aging: Molecular Mechanisms and Translational Implications. Trends Mol Med. 2017;23(10):899-916. doi:10.1016/j.molmed.2017.08.001 
8. Kratz EM, Kokot I, Dymicka-Piekarska V, Piwowar A. Sirtuins-The New Important Players in Women's Gynecological Health. Antioxidants (Basel). 2021;10(1):84. Published 2021 Jan 10. doi:10.3390/antiox10010084 
9. Fu M, Liu M, Sauve AA, et al. Hormonal control of androgen receptor function through SIRT1. Mol Cell Biol. 2006;26(21):8122-8135. doi:10.1128/MCB.00289-06 
10. Penning TM. Human hydroxysteroid dehydrogenases and pre-receptor regulation: insights into inhibitor design and evaluation. J Steroid Biochem Mol Biol. 2011;125(1-2):46-56. doi:10.1016/j.jsbmb.2011.01.009 
11. Rasmussen MK, Ekstrand B, Zamaratskaia G. Regulation of 3β-hydroxysteroid dehydrogenase/Δ⁵-Δ⁴ isomerase: a review. Int J Mol Sci. 2013;14(9):17926-17942. Published 2013 Sep 2. doi:10.3390/ijms140917926 
12. Rasmussen MK, Ekstrand B, Zamaratskaia G. Regulation of 3β-hydroxysteroid dehydrogenase/Δ⁵-Δ⁴ isomerase: a review. Int J Mol Sci. 2013;14(9):17926-17942. Published 2013 Sep 2. doi:10.3390/ijms140917926 
13. Cordeiro A, de Souza LL, Oliveira LS, et al. Thyroid hormone regulation of Sirtuin 1 expression and implications to integrated responses in fasted mice. J Endocrinol. 2013;216(2):181-193. Published 2013 Jan 18. doi:10.1530/JOE-12-0420 
14. Lee K, Choi GH, Back K. Functional Characterization of Serotonin N-Acetyltransferase in Archaeon Thermoplasma volcanium. Antioxidants (Basel). 2022;11(3):596. Published 2022 Mar 21. doi:10.3390/antiox11030596 
15. Huang H. A Multicentre, Randomised, Double Blind, Parallel Design, Placebo Controlled Study to Evaluate the Efficacy and Safety of Uthever (NMN Supplement), an Orally Administered Supplementation in Middle Aged and Older Adults. Front Aging. 2022;3:851698. Published 2022 May 5. doi:10.3389/fragi.2022.851698 
16. Kim M, Seol J, Sato T, Fukamizu Y, Sakurai T, Okura T. Effect of 12-Week Intake of Nicotinamide Mononucleotide on Sleep Quality, Fatigue, and Physical Performance in Older Japanese Adults: A Randomized, Double-Blind Placebo-Controlled Study. Nutrients. 2022;14(4):755. Published 2022 Feb 11. doi:10.3390/nu14040755 
17. Bertoldo MJ, Listijono DR, Ho WJ, et al. NAD+ Repletion Rescues Female Fertility during Reproductive Aging. Cell Rep. 2020;30(6):1670-1681.e7. doi:10.1016/j.celrep.2020.01.058 

Written by: Joe Condora 

Reviewed by: Heather L. Makar