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October 13, 2021

Menopause Part 7: Beyond Hormone Testing

Welcome to part 7 of the ODX Menopause Series. This post covers common biochemical changes, beyond estrogen and progesterone, that are associated with menopause. Identifying and addressing these changes can help reduce risk of chronic disease down the road.

The ODX Menopause Series

  1. Menopause Part 1: A Quick Overview of a Slow Process
  2. Menopause Part 2: Biology and Physiology of Menopause
  3. Menopause Part 3: Increased Risk of Disease Associated with Menopause
  4. Menopause Part 4: Identifying Menopause: Signs and Symptoms
  5. Menopause Part 5: Laboratory Evaluation of Menopause
  6. Menopause Part 6: Cardiovascular Risk in Menopause
  7. Menopause Part 7: Beyond Hormone Testing in Menopause
  8. Menopause Part 8: Natural Approaches to Menopause
  9. Menopause Part 9: Diet and Nutrition Intervention in Menopause
  10. Menopause Part 10: Characteristic of Herbal Derivatives used to Alleviate Menopause Symptoms
  11. Menopause Part 11: Lifestyle Approaches to Menopause
  12. Menopause Part 12: The National Institute on Aging Addresses Hot Flashes
  13. Menopause Part 13: Hormone Replacement Therapy (HRT) in Menopause
  14. Menopause Part 14: North American and European Guidelines for Hormonal Management of Menopause
  15. Menopause Part 15: Bioidentical Hormone Therapy
  16. Menopause Part 16: Optimal Takeaways for Menopause
  17. Optimal The Podcast - Episode 10

Biomarkers associated with chronic disease and inflammation should be incorporated into a comprehensive assessment of menopause. Early identification of risk factors provides the patient and practitioner the opportunity to address and modify risk early on.

Adipokines

Adipose tissue is now recognized as a metabolically active endocrine organ containing mature and premature adipocytes, endothelial cells, fibroblasts, and immune cells including mast cells. Adipokines are biologically active molecules that are produced primarily in adipose tissue but have systemic effects on inflammation, and lipid and glucose metabolism. Adipokine balance can become impaired as adipose tissue expands, and this imbalance contributes to a “metabolically unhealthy” obese state. A pro-inflammatory profile contributes to cardiovascular disease, metabolic syndrome, and type 2 diabetes.[1]

Main adipokines are:

  • Adiponectin
  • Chemokine ligand 2
  • Interleukin-6. Interleukin-10
  • Leptin
  • Resistin
  • Transforming growth factor-B
  • Tumor-necrosis factor

Adipokines participate in regulation of blood pressure, blot clotting, immune function, inflammatory reactions, and lipoprotein metabolism. Notable changes in adipokine production occur in menopause. These changes are characterized by biochemical shifts that can be monitored:[2]  

  • Significant increases in leptin and resistin
  • Downregulation of adiponectin and ghrelin
  • Increased associated risk of dyslipidemia, hypertension, osteoporosis, and CVD

Leptin in Menopause

Leptin levels correlate with inflammation and are increased in chronic inflammatory disorders.[3]

Increased leptin correlates with increased abdominal obesity, visceral fat, and waist-to-hip ratio. Metabolic syndrome is associated with elevated leptin as well. In one study of 153 postmenopausal women, those with metabolic syndrome had significantly higher leptin. Levels correlated with increased visceral fat, abdominal obesity, and waist-to-hip ratio after adjustment for BMI.[4] Monitoring leptin levels during menopause may help assess cardiometabolic disease risk in postmenopausal women.

Adiponectin in Menopause

Researchers suggest that assessing adiponectin may be a good screening tool for metabolic syndrome during the menopausal period, especially when increased abdominal adiposity is present.

In a cross-sectional study of 290 peri- and postmenopausal women, adiponectin was significantly lower in those with metabolic syndrome at a mean level of 6.0 versus 9.2 ug/mL. Subjects in the lowest quartile of adiponectin (less than 4.5 ug/mL) also had significantly higher fasting glucose and triglycerides, and significantly lower HDL than those in the highest quartile (greater than 11.3 ug/mL). Researchers suggest that an adiponectin of less than 7.15 ug/mL is indicative of metabolic syndrome. Low levels of adiponectin can lead to:[5]

  • Increased TNF-alpha and IL-6 from macrophages
  • Chronic inflammation and insulin resistance
  • Increased gluconeogenesis and hyperglycemia
  • Decreased transport of free fatty acids within the cell
  • Decreased anti-inflammatory IL-10 and IL-1-receptor antagonist
  • Loss of adiponectin’s anti-inflammatory effects on macrophages, cardiac muscle cells, fibroblasts, and the endothelium.

Anti-Mullerian Hormone in Menopause

Anti-Mullerian hormone (AMH) may provide insight into the timing of menopause, including premature ovarian failure. It is considered a very stable marker and levels will begin to decline earlier than FSH and inhibins. Levels of AMH may become barely detectable five to six years prior to full menopause.

Researchers found AMH decreased from above 1.5 ng/mL (10.7 pmol/L) to less than 0.2 ng/mL (1.4 pmol/L) approximately 5.99 years prior to menopause in women 45-48 years, and 9.94 years prior in women 35-39. Smoking will magnify decreases in AMH and can hasten menopause by up to three years.[6]

Bone markers in Menopause

Osteoporosis and related fractures are of significant concern in the postmenopausal period and outweigh the incidence of myocardial infarction, stroke, and breast cancer in this group combined.[7]

Bone mineral density can be assessed using bone density scans, though they may not reflect subtle changes in bone metabolism. Monitoring bone turnover markers in those at elevated risk for osteoporosis or those receiving therapy may be useful.

Since estrogen inhibits bone breakdown, its protective effects are diminished in menopause and increased bone breakdown by osteoclasts is observed. Elevations in bone matrix peptides such C-terminal telopeptide (CTX) and procollagen type I N-terminal propeptide (P1NP), osteocalcin, bone-specific alkaline phosphatase should be further evaluated and addressed appropriately. Ideally a series of results should be compared to baseline in order to determine pathological trends, or response or resistance to treatment.[8]

The Association for Clinical Biochemistry & Laboratory Medicine summarizes changes in serum markers that represent increased risk of bone loss after menopause.[9]

Serum Biomarker

Premenopausal

Postmenopausal

CTX

 

0.19 ng/mL

0.31 ng/mL

P1NP

 

30.1 ng/mL

41.3 ng/mL

Bone alkaline phosphatase

 

9.8 ng/mL

14.1 ng/mL

 

Osteocalcin

 

17.9 ng/mL

24.5 ng/mL

25-OH vitamin D

 

31.5 ng/mL

78.6 nmol/L

26.5 ng/mL

66 nmol/L

PTH

27 pg/mL

 

34.9 pg/mL

Homocysteine in Menopause

Postmenopausal status (55 years or older) is associated with elevated homocysteine, a biomarker associated with increased risk of hypertension and CVD. Elevated homocysteine itself is associated with decreased HDL, vitamin C, red blood cell folate, and serum folate and B12. Intake of vitamin and mineral supplements is associated with a decrease in homocysteine levels.[10]

Alterations in homocysteine metabolism observed across stages of menopausal transition can contribute to endothelial dysfunction and its cardiovascular complications. In one study of healthy women categorized as pre-, peri-, and postmenopausal, declining estradiol was associated with an elevation in homocysteine and cysteine. Both biomarkers are associated with endothelial dysfunction. In this study, homocysteine and cysteine were inversely correlated with estradiol, glutathione, brachial artery flow-mediated dilation, and intake of vitamins B6 and B12. Elevations in homocysteine and cysteine were correlated with elevations in oxidized LDL as well, increasing risk of atherosclerosis and CVD.[11]

Oxidative Stress in Menopause

Oxidative stress is a recognized risk factor for chronic disease including atherosclerosis, CVD, vasomotor disorders, and neurological disease. Menopause has been associated with an increase in oxidative stress, possibly due to loss of the antioxidant effects of estrogen. A case-controlled study of 50 postmenopausal and 48 premenopausal women demonstrated a significantly lower serum total antioxidant capacity, and significantly higher level of the oxidative stress marker malondialdehyde, in the postmenopausal group.[12]

Increases in glycation end-products (AGEs) and other oxidative stress biomarkers are observed with menopause and associated with increased risk of subclinical atherosclerosis:[13]

  • Significantly higher AGEs were observed in women with higher testosterone of 53-60 ng/dL (1.7-5.6 nmol/L) versus lower testosterone of 23-52 ng/dL (0.8-1.8 nmol/L).
    • Increased free androgen index (FAI), was also associated with increased AGEs The correlation remained highly significant even after adjustment for HOMA-IR, fasting glucose and insulin, age, and BMI.[14]
  • Asymmetric dimethylarginine (ADMA), which inhibits nitric oxide synthase, increased with BMI in postmenopausal women.
  • Ischemia modified albumin (modified by oxygen free radicals) was elevated in obese postmenopausal women.
  • Oxidative stress itself contributes to CVD, diabetes, hypercholesterolemia, and hypertension.

Monitoring gamma-glutamyltransferase (GGT) can help assess risk of oxidative stress and metabolic dysfunction as well. Increased serum GGT is associated with increased glutathione metabolism, decreased glutathione levels, and increased oxidative stress.[15] Levels above 16.5 U/L are associated with metabolic syndrome and above 20.5 U/L are associated with impaired glucose tolerance.[16]

Oxidative stress appears to contribute to postmenopausal osteoporosis (PO). A systemic review and meta-analysis revealed that those with PO had: [17]

  • Significantly elevated oxidative stress index, malondialdehyde, advanced oxidation protein products, and vitamin B12.
  • Decreased total antioxidant status, total antioxidant power, catalase, glutathione peroxidase, uric acid, and folate.

Sex Hormone Binding Globulin in Menopause

A prospective longitudinal cohort study of 172 women found that while testosterone did not change from the pre- to postmenopausal period, SHBG decreased by 43% from 4 years prior to their final menstrual period to two years after. This shift increased the free androgen index by 80% during this period. The decreased SHBG and increased FAI correlated with an increase in BMI. Lower levels of DHEAS were also associated with a higher BMI.[18]

Decreased SHBG and higher BMI are associated with increased risk of metabolic syndrome in postmenopausal women. Evaluation of data from the Women’s Health Study revealed that 51% of postmenopausal women, not on hormone therapy, met the criteria for metabolic syndrome. This group had significantly lower SHBG, higher BMI, more cardiovascular events, and significantly higher estradiol, testosterone, and free androgen index:[19]

TSH in Menopause

Some symptoms of menopause overlap with those of thyroid dysfunction which should be ruled out. Thyroid stimulating hormone (TSH) levels are positively associated with dyslipidemia in postmenopausal women e.g., elevated triglycerides, LDL, and total cholesterol. Because iodine uptake into the thyroid gland decreases during menopause, production of thyroid hormone decreases and in response, TSH increases. Thyroid hormones exert specific effects including:[20]

  • Increases synthesis of androgens, thyroid-binding globulin, and SHBG
  • Reduces sex steroid clearance
  • Stimulates aromatase

Vitamin D in Menopause

Vitamin D insufficiency is common in menopause and is associated with autoimmunity, cancer, diabetes, hypertension hypertriglyceridemia, immune compromise, impaired calcium metabolism, inflammation, metabolic syndrome, multiple sclerosis, osteoporosis risk, psoriasis, and rheumatoid arthritis.[21] Low serum 25(OH) vitamin D is also associated with depression and impaired cognition, also commonly observed with menopause.[22]

Low levels of 25(OH)D are also correlated with increased bone turnover in postmenopausal women. In one double-blind placebo-controlled study, supplementation with 1000 IU/day of vitamin D resulted in increased serum 25(OH)D from 15 ng/mL (37.4 nmol/L) to 27.5 ng/mL (68.6 nmol/L), along with decreases in serum PTH, CTX, and P1NP.[23] It is noted that levels did not reach the minimum recommended functional level of 40 ng/mL (100 nmol/L).[24]

Ensuring optimal vitamin D status with levels maintained between 50-90 ng/mL (125-225 nmol/L) can help minimize the risk of many chronic conditions associated with menopause. Therefore, vitamin D status should be monitored regularly in menopause and beyond.

References

[1] Pereira, Solange Silveira, and Jacqueline I. Alvarez-Leite. "Adipokines: biological functions and metabolically healthy obese profile." Journal of receptor, ligand and channel research 7 (2014): 15-25.

[2] Ko, Seong-Hee, and Hyun-Sook Kim. “Menopause-Associated Lipid Metabolic Disorders and Foods Beneficial for Postmenopausal Women.” Nutrients vol. 12,1 202. 13 Jan. 2020, doi:10.3390/nu12010202

[3] Iikuni, Noriko et al. “Leptin and Inflammation.” Current immunology reviews vol. 4,2 (2008): 70-79. doi:10.2174/157339508784325046

[4] Lee, S W et al. “Association between metabolic syndrome and serum leptin levels in postmenopausal women.” Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology vol. 32,1 (2012): 73-7. doi:10.3109/01443615.2011.618893

[5] Wattanapol, Puntabut et al. “Serum adiponectin is a potential biomarker for metabolic syndrome in peri-and postmenopausal women.” Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology vol. 36,7 (2020): 620-625. doi:10.1080/09513590.2020.1742688

[6] Kruszyńska, Aleksandra, and Jadwiga Słowińska-Srzednicka. “Anti-Müllerian hormone (AMH) as a good predictor of time of menopause.” Przeglad menopauzalny = Menopause review vol. 16,2 (2017): 47-50. doi:10.5114/pm.2017.68591

[7] Hymavathi, K., Tejaswini Jakka, and Bhaavya Paturi. "Correlation of biomarkers and bone mineral density for osteoporosis in post-menopausal women." International Journal of STRion, Contraception, Obstetrics and Gynecology 9.2: 721.

[8] Pagana, K. D., & Pagana, T. J. (2017). Mosby's Manual of Diagnostic and Laboratory Tests-E-Book. Elsevier Health Sciences.

[9] Honour, John W. “Biochemistry of the menopause.” Annals of clinical biochemistry vol. 55,1 (2018): 18-33. doi:10.1177/0004563217739930

[10] Lim, Unhee, and Patricia A Cassano. “Homocysteine and blood pressure in the Third National Health and Nutrition Examination Survey, 1988-1994.” American journal of epidemiology vol. 156,12 (2002): 1105-13. doi:10.1093/aje/kwf157

[11] Keller, Amy C et al. “Elevated plasma homocysteine and cysteine are associated with endothelial dysfunction across menopausal stages in healthy women.” Journal of applied physiology (Bethesda, Md. : 1985) vol. 126,6 (2019): 1533-1540. doi:10.1152/japplphysiol.00819.2018

[12] Zovari, Fatemeh et al. “Evaluation of Salivary and Serum Total Antioxidant Capacity and Lipid Peroxidation in Postmenopausal Women.” International journal of dentistry vol. 2020 8860467. 17 Nov. 2020, doi:10.1155/2020/8860467

[13] Honour, John W. “Biochemistry of the menopause.” Annals of clinical biochemistry vol. 55,1 (2018): 18-33. doi:10.1177/0004563217739930

[14] Diamanti-Kandarakis, Evanthia et al. “Androgens associated with advanced glycation end-products in postmenopausal women.” Menopause (New York, N.Y.) vol. 17,6 (2010): 1182-7. doi:10.1097/gme.0b013e3181e170af

[15] Bradley, Ryan et al. “Associations between total serum GGT activity and metabolic risk: MESA.” Biomarkers in medicine vol. 7,5 (2013): 709-21. doi:10.2217/bmm.13.71

[16] Yousefzadeh, Gholamreza et al. “Role of gamma-glutamyl transferase (GGT) in diagnosis of impaired glucose tolerance and metabolic syndrome: a prospective cohort research from the Kerman Coronary Artery Disease Risk Study (KERCADRS).” Diabetes & metabolic syndrome vol. 6,4 (2012): 190-4. doi:10.1016/j.dsx.2012.08.013

[17] Zhao, Fulong et al. “Correlation of oxidative stress-related biomarkers with postmenopausal osteoporosis: a systematic review and meta-analysis.” Archives of osteoporosis vol. 16,1 4. 5 Jan. 2021, doi:10.1007/s11657-020-00854-w

[18] Burger, H G et al. “A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition.” The Journal of clinical endocrinology and metabolism vol. 85,8 (2000): 2832-8. doi:10.1210/jcem.85.8.6740

[19] Weinberg, Melissa E et al. “Low sex hormone-binding globulin is associated with the metabolic syndrome in postmenopausal women.” Metabolism: clinical and experimental vol. 55,11 (2006): 1473-80. doi:10.1016/j.metabol.2006.06.017

[20] Honour, John W. “Biochemistry of the menopause.” Annals of clinical biochemistry vol. 55,1 (2018): 18-33. doi:10.1177/0004563217739930

[21] Ko, Seong-Hee, and Hyun-Sook Kim. “Menopause-Associated Lipid Metabolic Disorders and Foods Beneficial for Postmenopausal Women.” Nutrients vol. 12,1 202. 13 Jan. 2020, doi:10.3390/nu12010202

[22] Lerchbaum, Elisabeth. “Vitamin D and menopause--a narrative review.” Maturitas vol. 79,1 (2014): 3-7. doi:10.1016/j.maturitas.2014.06.003

[23] Pérez-López, Faustino R et al. “Vitamin D supplementation after the menopause.” Therapeutic advances in endocrinology and metabolism vol. 11 2042018820931291. 5 Jun. 2020, doi:10.1177/2042018820931291

[24] Cannell, John J, and Bruce W Hollis. “Use of vitamin D in clinical practice.” Alternative medicine review : a journal of clinical therapeutic vol. 13,1 (2008): 6-20.

Tag(s): Biomarkers

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