EDITORIAL

Behavior, Hormones, and Cardiovascular Disease:Interpretations and Implications

The study described by Kaplan et al in this issue of Obstetrics & Gynecology providesnovel information about the interaction between behavior, reproductive hormones,and cardiovascular disease in premenopausal cynomolgus monkeys.1 To recapitu-late, in this meticulously done experiment, the investigators found that subordinatefemale monkeys developed more atherosclerosis than dominant monkeys in theabsence of obvious reproductive compromise. The first question that one might askis why subordination is atherogenic. The authors suspect that it is the presence ofoccult hypoestrogenism. This interpretation is based, in part, on the observation thatwhile monkeys in both social groups remained eumenorrheic, progesterone levelswere somewhat lower in the subordinates relative to the dominants. However,fertility was not tested and estradiol secretion across a menstrual interval was notcharacterized. Thus, the degree of hypoestrogenism is not well described. As theauthors note in the discussion, the stress of subordination causes other hormonalperturbations other than occult hypogonadism. In particular, subordinate monkeysare likely to be hypercortisolemic.2 Because cortisol can impair thyrotropin-releasinghormone drive and the thyroidal response to thyroid-stimulating hormone, thesubordinate monkeys presumably also suffer from relative hypothyroidism. Possi-bly there are other metabolic adaptations that transpire in subordinates as they copewith the stress of their position.3,4 None of these hormonal patterns was character-ized in this study. The primary reason the authors suspect occult hypogonadismrather than the metabolic concomitants of stress as the cause of the acceleratedatherogenesis is that treating the subordinates with oral contraceptives prevented it.This interpretation rests on the assumption that provision of oral contraceptivesaltered only sex steroid levels. However, sex steroid levels may modulate theendocrine response to the stress. For instance, the response to some stressors, such asendotoxin, is blunted by sex steroids,5 while the response to restraint stress isheightened if the ovaries are present.6 Even more intriguing is the demonstrationthat lactation renders women hyporeactive to the endocrine effects of exercisestress.7 In short, oral contraceptive exposure may have blunted the subordinates’endocrine responses to social stress. The only way to know is to compare endocrinereactivity to social stress in monkeys exposed to oral contraceptives. One wouldpredict that dominants are less reactive than subordinates regardless of oral contra-ceptive exposure and that subordinates treated with oral contraceptives would beless reactive than those not treated. Thus, an alternate hypothesis is that oralcontraceptive exposure blunts the endocrine responses of subordinates to stress,making them comparable to those of dominants.

How might these data relate to clinical practice? Is the monkey model relevant tothe human situation? Should we then recommend that our patients take oralcontraceptives to interdict the effects of stressors? Because the experimental para-digm was imposed on the monkeys, they could not readily escape from their stressfulsituation as they might have done under naturalistic conditions. Interestingly, theauthors note that changes in the group due to illness often led to a change in social

Sarah L. Berga, MD

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status for some of the monkeys. In the human state, wepresumably have options on changing our social groupswhen we find ourselves in a chronically stressful predic-ament. Without belaboring the obvious, it is probablybetter to learn to cope with stress, including learning howto escape from it, rather than to stay put and blunt theendocrine effects of stress with medications, even if, as isthe case for oral contraceptives, the medication has otherdesired effects.

REFERENCES

1. Kaplan JR, Manuck SB, Anthony MS, Clarkson TB. Pre-menopausal social status and hormone exposure predictpostmenopausal atherosclerosis in female monkeys. ObstetGynecol 2002; 99:381–8.

2. Kaplan JR, Adams MR, Koritnik DR, Rose JC, Manuck SB.Adrenal responsiveness and social status in intact and ovari-ectomized Macaca fascicularis. Am J Primatol 1986;11:181–93.

3. Berga SL, Mortola JF, Girton L, Suh B, Laughlin GA, PhamP, Yen SSC. Neuroendocrine aberrations in women withfunctional hypothalamic amenorrhea. J Clin EndocrinolMetab 1989;68:301–8.

4. Laughlin GA, Dominguez CE, Yen SSC. Nutritional andendocrine-metabolic aberrations in women with functionalhypothalamic amenorrhea. J Clin Endocrinol Metab 1998;83:25–32.

5. Xiao E, Xia-Zhang L, Ferin M. Stress and the menstrualcycle: Short- and long-term response to a five-day endotoxinchallenge during the luteal phase in the rhesus monkey.J Clin Endocrinol Metab 1999;84:623–6.

6. Chen MD, O’Bryne KT, Chiappini SE, Hotchkiss J, KnobilE. Hypoglycemic ‘stress’ and gonadotropin-releasing hor-mone pulse generator activity in the rhesus monkey: Role ofthe ovary. Neuroendocrinology 1992;56:666–73

7. Altemus M, Deuster PA, Galliven E, Carter CS, Gold PW.Suppression of hypothalamic-pituitary-adrenal axis responsesto stress in lactating women. J Clin Endocrinol Metab1995;80:2954–9.

374 Berga Behavior, Hormones, Cardiovascular Disease OBSTETRICS & GYNECOLOGY