14 January 2019: 

Perimenopause marks the initiation of the transition into female reproductive senescence. It is well known that in general, the age at onset and duration of the menopause transition are associated with heritage on the one hand, but with many environmental, socioeconomic, lifestyle and other extrinsic factors on the other hand (1). Entering natural menopause at an early age carries potential long-term higher risks for chronic diseases, such as coronary heart disease and osteoporosis. Thus, prediction of the age at menopause might be important, allowing those with a forecast for premature or early menopause to be well prepared for such a scenario (2). What seems to be more challenging is whether we can manipulate the time sequence and delay menopause transition in women prone to early ovarian failure and the resultant rapid decline in estrogen production. The human genome, our basic genetic code, is largely static within an individual, yet chemical changes to the DNA and histone proteins may occur frequently as a result of what is defined as epigenetic alterations. This means that epigenomic deviations can result in changes to the structure of chromatin and to the function of the genome. To note, the epigenome can be dynamically altered by environmental conditions. A new study in rats claimed that understanding the hypothalamic neuroendocrine derangements which occur prior to the appearance of early signs of oocyte exhaustion could lead to the development of active interventions that will impact these complex mechanisms and delay the menopause by maintaining the normal hormonal milieu (3).

Here are some basic physiological facts: S-adenosylmethionine (SAM), the universal methyl-donor that provides methyl-groups used for DNA, histone, and other protein methylation, is produced from the functional one-carbon cycle. The one-carbon cycle uses co-factors such as folate, choline, and various other B vitamins (B6, B12, riboflavin) to recycle homocysteine to produce SAM. Breakdown of the one-carbon cycle results in decreased production of SAM and an accumulation of the intermediate molecule, homocysteine. Failure to produce sufficient levels of SAM can lead to global decline of DNA and histone methylation, resulting in dysregulation of the epigenome. A thorough investigation of the various relevant pathways in rats were summarized in Bacon et al as follows (3): 1) hypothalamic aging begins before the phenotypic manifestation of perimenopause, altered hypothalamic-pituitary-gonadal signaling precedes ovarian aging, hypothalamic aging precedes hippocampal aging, 2) Accelerated epigenomic aging is evident in early transitioners, 3) Treatment with epigenetic modifiers impacts the timing of reproductive senescence with inhibition of DNA methylation accelerating endocrine aging, whereas promoting DNA methylation with methionine delays endocrine aging.

What is known in women? Women with an earlier age at menopause onset were found to be “epigenetically older” than women with a later onset despite being the same chronological age (4). Methylation reactions linked to homocysteine in the one-carbon metabolism are related to early menopause. Hyperhomocysteinemia and DNA hypomethylation induced by B vitamin deficiency may be an underlying mechanism. Therefore, initiation of interventions to sustain epigenetic mechanisms, specifically DNA methylation, could be a strategy to prevent or at least delay reproductive/endocrine aging in women. Based on the above data, it is quite surprising that SAM supplementation has not been investigated as a potential candidate to tackle early menopause. SAM, S-adenosylmethionine, may be bought in food stores and pharmacies without a prescription and is used by many in various indications, such as malignancies, Alzheimer’s disease, fibromyalgia and osteoarthritis (5). I guess the remaining problem is how to detect women at risk for early menopause long before the appearance of the typical signs of perimenopause. Perhaps a score, including relevant family history, Anti Mullerian Hormone level as well as other neuroendocrine parameters, and specific blood tests that evaluate the DNA methylation status as a biomarker could be used, and hence only the identified subset of women at high-risk may perhaps be recommended for treatment.

Amos Pines

References

1. Costanian C, McCague H, Tamim H. Age at natural menopause and its associated factors in Canada: cross-sectional analyses from the Canadian Longitudinal Study on Aging. Menopause 2018;25:265-72. 
   https://www.ncbi.nlm.nih.gov/pubmed/28968303
2. Depmann M, Eijkemans MJC, Broer SL, et al. Does AMH relate to timing of menopause? Results of an Individual Patient Data meta- analysis. J Clin Endocrinol Metab 2018 Jul 18. 
   https://www.ncbi.nlm.nih.gov/pubmed/30032277
3. Bacon ER, Mishra A, Wang Y, Desai MK, Yin F, Brinton RD. Neuroendocrine aging precedes perimenopause and is regulated by DNA methylation. Neurobiol Aging 2018; 74:213-24. 
   https://www.ncbi.nlm.nih.gov/pubmed/30497015
4. Levine ME, Lu AT, Chen BH, et al. Menopause accelerates biological aging. Proc Natl Acad Sci. U. S. A. 2016; 113: 9327-32. 
   https://www.ncbi.nlm.nih.gov/pubmed/27457926
5. WebMD website 
   https://www.webmd.com/vitamins/ai/ingredientmono-786/same