Differential effects of western versus mediterranean diets and psychosocial stress on ovarian function in female monkeys (Macaca fascicularis)

Abstract

Ovarian dysfunction increases risk for chronic diseases of aging including cardiovascular disease, depression, cognitive impairment, as well as bone and muscle loss which promote frailty. Psychosocial stress can disrupt ovarian function, and recent observations suggest that consumption of a Western Diet may also. Determination of causal relationships among diet, psychosocial stress, and ovarian physiology is difficult in humans. Long-tailed (a.k.a. cynomolgus) macaques (Macaca fascicularis) are an excellent translational model for the study of diet and psychosocial effects on ovarian physiology and aging-related processes. They have 28-day menstrual cycles with hormonal fluctuations like those of women, and similar physiologic responses to alterations and/or cessation of cyclicity. We examined ovarian function in 38 middle-aged socially housed females fed either a Western or Mediterranean diet for 31 months (≈ a 9-year period for humans). During the last year, we examined cycle length and peak progesterone per cycle using blood sampling (3/week) and vaginal swabbing for menses (6/week). Repeated measures analysis revealed a circannual pattern consistent with increased menstrual cycle disturbance during the late Summer and early Fall (F(11,348)= 4.05 p < 0.001). In addition, both Western diet (F(1,34)= 3.99; p = 0.05) and the stress of low social status (F(1,34)= 3.99; p = 0.04) reduced mean progesterone levels. Thus, on average, subordinates in the Western group had the lowest average progesterone levels (10.02 ng/pl). Compared to Western diets, Mediterranean diets exhibited protective effects via menstrual cycle regularity. For dominant monkeys, consuming Mediterranean diets resulted in significantly greater likelihood of having regular menstrual cycles. Mediterranean diets also protected individuals from shorter than normal menstrual cycles. The relationships between diet and menstrual regularity were partially mediated by both adrenal reactivity and social isolation. This study demonstrates the additive negative effects of poor diet and psychosocial stress on ovarian physiology in mid-life and lays the groundwork for future investigations to uncover their impact on metabolic signatures of accelerated aging. The results also suggest that - compared to Western-style diets - a Mediterranean diet may exert a protective influence against ovarian dysfunction and its pathologic sequelae.

Keywords: Mediterranean diet; Nonhuman primate; Ovarian cycling; Progesterone; Psychosocial stress.

Figure 1.

Effects of diet, social status, and time on luteal phase progesterone over the course of the dietary intervention. Progesterone significantly varied over time, including a seasonal depression of progesterone profiles during the months of August, September, and October (Time: F(11,348)=4.05; p<0.001). Socially dominant monkeys had higher levels of progesterone than socially subordinate monkeys (Status: F(1,34)=4.32; p=0.04). Monkeys consuming the Mediterranean diets had higher progesterone profiles compared to monkeys consuming the Western diet (Diet: F(1,34)=3.99; p=0.05). Thus, dominant monkeys consuming the Mediterranean diet had the highest progesterone levels whereas subordinate monkeys consuming the Western diet had the lowest (Holm-Corrected Pairwise Comparison: t=3.02, p=0.03).

Figure 2.

Interaction of diet and social status on menstrual cycle regularity (Diet x Status: β=1.98 p=0.02). A) Dominant monkeys consuming the Mediterranean diet were significantly more likely to exhibit a regular menstrual cycle (25-33 days) compared to dominants consuming Western diets (p_bonf=0.02). B & C) For both dominants (Fisher’s Exact Test: p= 0.02) and subordinates (Fisher’s Exact Test: p= 0.01), consumption of the Mediterranean diet significantly reduced the number of short menstrual cycles. Sample Sizes: Western diet N=21 (10 subordinate, 11 dominant); Mediterranean N=17 (7 subordinate, 10 dominant)

Figure 3.

Forest plot of mediation analyses for the partial mediation effects of A) adrenocortical reactivity and B) rate of time spent alone on the effects of diet on the number of irregular menstrual cycles during the Treatment period. Of the increased in likelihood of having an irregular cycle due to Western diet, ~39% was due to adrenocortical reactivity and ~36% of the increases were due to adrenocortical reactivity and rates of time spent alone, respectively. Sample Sizes: Western diet N=21 (10 subordinate, 11 dominant); Mediterranean N=17 (7 subordinate, 10 dominant)