Influence of Menopause

Key Points

• Abdominal (visceral) adiposity increases with the onset of menopause.
• Abdominal tissue redistribution with menopause appears to be independent of age and total body fat and could be related to a relative deficit in estrogens.
• Menopause has a negative impact on plasma lipoprotein-lipid levels, which may increase CVD risk.
• HTR in post-menopausal women helps protect against intra-abdominal fat accumulation. However, prospective studies that have assessed “hard” CVD endpoints have failed to confirm HRT’s benefits. Current evidence does not support the use of HRT to reduce menopause-related CVD risk.

The Influence of Menopause on Adipose Tissue Distribution

The physiological changes associated with menopause have a significant impact on total body fat and adipose tissue distribution. Because intra-abdominal adipose tissue deposition in women is also influenced by age, it is important to consider this variable when discussing the influence of menopause on adipose tissue distribution.  

Several cross-sectional studies have reported a significant difference in body mass index (BMI)—a crude marker of obesity—between pre-menopausal and post-menopausal women that was no longer significant after adjusting for age (1, 2). However, other studies have found that menopause has a significant effect on BMI independent of age (3-5). Some studies that have used dual energy X-ray absorptiometry (DEXA) to measure total body fat more precisely have found that menopause has no significant effect on total body fat (4, 6), whereas other groups have reported that post-menopausal women were heavier than pre-menopausal women after adjusting for age (7, 8).

The central accumulation of body fat with menopause, as assessed by anthropometric measurements or imaging techniques, is a well described phenomenon. Several cross-sectional studies that have used waist-to-hip ratio or waist circumference as estimates of relative or absolute accumulation of abdominal fat respectively have failed to link abdominal adipose tissue accumulation and menopause (2-4, 9-11). Even after controlling for age or BMI, no association between menopause and abdominal obesity has been found (3, 11, 12). However, by using DEXA to measure abdominal adipose tissue (trunkal fat), several investigators have noted that menopause has an independent effect on adipose tissue distribution even after controlling for age (8, 13) and BMI (1, 6) .

Figure 1: Increase in intra-abdominal adipose tissue (AT) accumulation associated with menopause

Figure 1: Increase in intra-abdominal adipose tissue (AT) accumulation associated with menopause

It is the use of precise imaging techniques to measure subcutaneous vs. intra-abdominal (visceral) adipose tissue depots that has conclusively shown that menopause has an independent effect on adipose tissue distribution even after correcting for age (14) and BMI (12). In this regard, Kotani et al. (14) reported that intra-abdominal adipose tissue accumulates twice as fast in post-menopausal women as it does in pre-menopausal women. Other studies have also demonstrated that the ratio of abdominal subcutaneous to intra-abdominal adipose tissue was lower in post-menopausal women than in pre-menopausal women (15). Moreover, Toth et al. (16) noted that fat mass was 35% higher while intra-abdominal adipose tissue accumulation was 57% greater in post-menopausal women than in pre-menopausal women, lending further weight to the notion that adipose tissue accumulates selectively in the abdominal cavity with menopause. Figure 1 shows the increased accumulation of intra-abdominal adipose tissue distribution in post-menopausal women even without significant changes in BMI values when compared to pre-menopausal women (17).

Although cross-sectional studies provide relevant information on the “effect” of menopause on adipose tissue distribution, only longitudinal studies can provide a clear picture of the changes that occur in women going through menopause.

Unfortunately, only a few longitudinal studies have examined this issue. Several studies have reported increases in total body fat mass with age (18-20). In a six-year longitudinal study, Björkelund et al. (19) found that abdominal adipose tissue accumulated selectively in women who became post-menopausal when compared to women who remained pre-menopausal over the same period. Changes in adipose tissue distribution were observed using anthropometric measurements such as waist-to-hip ratio and waist circumference. In addition, BMI remained similar between post-menopausal and pre-menopausal women. Further longitudinal studies that use more accurate intra-abdominal fat measurement methods—such as magnetic resonance imaging or computed tomography—are needed to better describe the effect of menopause transition on body fat distribution.

As mentioned above, post-menopausal women are characterized by increased intra-abdominal adipose tissue accumulation when compared to pre-menopausal women. There is evidence that hormone replacement therapy (HRT), which is typically used for alleviating symptoms of menopause, can also limit intra-abdominal adipose tissue accumulation. HRT has been shown to modify abdominal fat distribution by reducing intra-abdominal adipose tissue in estrogen-supplemented post-menopausal women, as compared to controls receiving a placebo (10, 21). In fact, the administration of estrogens and progestins has been found to enhance lipoprotein lipase activity and lipid accumulation in the femoral region but not in the abdominal area (22). These results are consistent with the notion that sex steroids may play a major role in controlling regional adipose tissue accumulation.

Further studies are needed to better document the independent effect of menopause on intra-abdominal adipose tissue deposition. A key focus of these studies must be precise measurement of intra-abdominal adipose tissue. 

Metabolic Consequences of Adipose Tissue Redistribution After Menopause

Figure 2: Development of an atherogenic profile associated with menopause-related gain in intra-abdominal adiposity

Figure 2: Development of an atherogenic profile associated with menopause-related gain in intra-abdominal adiposity

As mentioned above, women generally accumulate more intra-abdominal adipose tissue as they go through menopause. It is unclear whether menopause is a cardiovascular risk factor for all women or only for those with the android pattern of adipose tissue distribution. However, it is well established that increasing intra-abdominal adipose tissue is one of the most prevalent manifestations of a cluster of abnormalities referred to as the metabolic syndrome, which predicts an increased cardiovascular disease risk (23). Some atherogenic metabolic changes associated with menopause are illustrated in Figure 2.

There is some debate about whether menopause increases the risk of cardiovascular disease independent of normal ageing (2, 24, 25). However, postmenopausal women have higher total cholesterol, increased LDL cholesterol and triglyceride as well as lower HDL (increased HDL₃ and decreased HDL₂) cholesterol levels than pre-menopausal women (26, 27). High levels of HDL₂ cholesterol appear to be responsible for the cardioprotective effect of HDL cholesterol. Substantial changes in LDL concentrations occur early in the transition from pre-menopause to post-menopause (28). The proportion of small, dense LDL particles also increases in women during this period (29). Menopause is therefore associated with the development of an atherogenic lipoprotein-lipid profile, which may raise coronary heart disease risk in post-menopausal women.

A few studies have examined the effect of menopause on insulin resistance. Several groups have shown that fasting insulin (2, 30) and glucose concentrations (30, 31) were higher in post-menopausal women than in pre-menopausal women. Toth et al. (16) found that the post-menopausal status per se was not associated with decreased insulin sensitivity, as assessed by the hyperinsulinemic-euglycemic clamp. Matthews et al. (24) also reported that menopause did not affect plasma glucose, insulin levels, body weight, and blood pressure. However, more work is clearly needed here to clarify the true impact of menopause on glucose-insulin homeostasis.

The reduction in intra-abdominal adipose tissue deposition observed with hormone replacement therapy in post-menopausal women is associated with a corresponding improvement in fasting lipid levels (except for triglycerides) (21). Several studies have noted a reduction in LDL cholesterol and a rise in HDL cholesterol levels following hormone replacement therapy (24, 32, 33). Accordingly, estrogen supplementation may be associated with a cardioprotective metabolic profile, although studies that have assessed “hard” cardiovascular (CVD) endpoints have failed to confirm this notion. This issue remains hotly debated in the literature.

In conclusion, the above observations support the notion that hormonally-induced redistribution of adipose tissue in the intra-abdominal (visceral) depots in post-menopausal women leads to adverse changes in the metabolic profile. Further research will enhance understanding of the influence of estrogens and hormone replacement therapy on fat tissue distribution and CVD risk factors.

References

1. Ley CJ, Lees B and Stevenson JC. Sex- and menopause-associated changes in body-fat distribution. American Journal of Clinical Nutrition 1992; 55: 950-4.
2. Razay G, Heaton KW and Bolton CH. Coronary heart disease risk factors in relation to the menopause. Q J Med 1992; 85: 889-96.
3. Pasquali R, Casimirri F, Labate AMM, et al. Body weight, fat distribution and the menopausal status in women. Int J Obes 1994; 18: 614-21.
4. Pasquali R, Vicennati V, Bertazzo D, et al. Determinants of sex hormone-binding globulin blood concentrations in premenopausal and postmenopausal women with different estrogen status. Virgilio-Menopause-Health Group. Metabolism 1997; 46: 5-9.
5. den Tonkelaar I, Seidell JC, van Noord PAH, et al. Fat distribution in relation to age, degree of obesity, smoking habits, parity and estrogen use: a cross-sectional study in 11825 Dutch women participating in the DOM-project. Int J Obes 1990; 14: 753-61.
6. Panotopoulos G, Ruiz JC, Raison J, et al. Menopause, fat and lean distribution in obese women. Maturitas 1996; 25: 11-9.
7. Rico H, Revilla M, Villa LF, et al. The four-compartment models in body composition: data from a study with dual-energy X-ray absorptiometry and near-infrared interactance on 815 normal subjects. Metabolism 1994; 43: 417-22.
8. Svendsen OL, Hassager C and Christiansen C. Age- and menopause-associated variations in body composition and fat distribution in healthy women as measured by dual-energy X-ray absorptiometry. Metabolism 1995; 44: 369-73.
9. Lanska DJ, Lanska MJ, Hartz AJ, et al. Factors influencing anatomic location of fat tissue in 52,953 women. Int J Obes 1985; 9: 29-38.
10. Tonkelaar ID, Seidell JC, van Noord PA, et al. Factors influencing waist/hip ratio in randomly selected pre- and post-menopausal women in the dom-project (preliminary results). Int J Obes 1989; 13: 817-24.
11. Troisi RJ, Wolf AM, Manson JE, et al. Relation of body fat distribution to reproductive factors in pre- and postmenopausal women. Obes Res 1995; 3: 143-51.
12. Zamboni M, Armellini F, Milani MP, et al. Body fat distribution in pre- and post-menopausal women: metabolic and anthropometric variables and their inter-relationships. Int J Obes Relat Metab Disord 1992; 16: 495-504.
13. Tremollieres FA, Pouilles JM and Ribot CA. Relative influence of age and menopause on total and regional body composition changes in postmenopausal women. Am J Obstet Gynecol 1996; 175: 1594-600.
14. Kotani K, Tokunaga K, Fujioka S, et al. Sexual dimorphism of age-related changes in whole-body fat distribution in the obese. Int J Obes 1994; 18: 207-12.
15. Enzi G, Gasparo M, Biondetti PR, et al. Subcutaneous and visceral fat distribution according to sex, age, and overweight, evaluated by computed tomography. Am J Clin Nutr 1986; 44: 739-46.
16. Toth MJ, Sites CK, Eltabbakh GH, et al. Effect of menopausal status on insulin-stimulated glucose disposal: comparison of middle-aged premenopausal and early postmenopausal women. Diabetes Care 2000; 23: 801-6.
17. Tchernof A, Desmeules A, Richard C, et al. Ovarian hormone status and abdominal visceral adipose tissue metabolism. J Clin Endocrinol Metab 2004; 89: 3425-30.
18. Akahoshi M, Soda M, Nakashima E, et al. Effects of menopause on trends of serum cholesterol, blood pressure, and body mass index. Circulation 1996; 94: 61-6.
19. Björkelund C, Lissner L, Andersson S, et al. Reproductive history in relation to relative weight and fat distribution. Int J Obes 1996; 20: 213-9.
20. Wing RR, Matthews KA, Kuller LH, et al. Weight gain at the time of menopause. Archives of Internal Medicine 1991; 151: 97-102.
21. Sumino H, Ichikawa S, Yoshida A, et al. Effects of hormone replacement therapy on weight, abdominal fat distribution, and lipid levels in Japanese postmenopausal women. Int J Obes Relat Metab Disord 2003; 27: 1044-51.
22. Rebuffé-Scrive M, Lonnroth P, Marin P, et al. Regional adipose tissue metabolism in men and postmenopausal women. Int J Obes 1987; 11: 347-55.
23. Després JP and Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006; 444: 881-7.
24. Matthews KA, Meilahn E, Kuller LH, et al. Menopause and risk factors for coronary heart disease. N Engl J Med 1989; 321: 641-6.
25. Kannel WB, Hjortland MC, McNamara PM, et al. Menopause and risk of cardiovascular disease: the Framingham study. Ann Intern Med 1976; 85: 447-52.
26. Stevenson JC, Crook D and Godsland IF. Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis 1993; 98: 83-90.
27. Jensen J, Nilas L and Christiansen C. Influence of menopause on serum lipids and lipoproteins. Maturitas 1990; 12: 321-31.
28. Matthews KA, Kuller LH, Sutton-Tyrrell K, et al. Changes in cardiovascular risk factors during the perimenopause and postmenopause and carotid artery atherosclerosis in healthy women. Stroke 2001; 32: 1104-11.
29. Campos H, McNamara JR, Wilson PW, et al. Differences in low density lipoprotein subfractions and apolipoproteins in premenopausal and postmenopausal women. J Clin Endocrinol Metab 1988; 67: 30-5.
30. Walton C, Godsland IF, Proudler AJ, et al. The effects of the menopause on insulin sensitivity, secretion and elimination in non-obese, healthy women. Eur J Clin Invest 1993; 23: 466-73.
31. Dallongeville J, Marecaux N, Isorez D, et al. Multiple coronary heart disease risk factors are associated with menopause and influenced by substitutive hormonal therapy in a cohort of French women. Atherosclerosis 1995; 118: 123-33.
32. Tikkanen MJ, Nikkila EA, Kuusi T, et al. High density lipoprotein-2 and hepatic lipase: reciprocal changes produced by estrogen and norgestrel. J Clin Endocrinol Metab 1982; 54: 1113-7.
33. Wilson PW, Garrison RJ and Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. The Framingham Study. N Engl J Med 1985; 313: 1038-43.