The Bruce Effect: Complementary Roles of Olfactory Memory and Male-Sourced Estradiol

Abstract

Uterine implantation of fertilized ova is a highly sensitive transition from minimal maternal investment to increasing devotion of resources to pregnancy. It involves a finely tuned interplay in the uterus between progesterone (P4) and the powerful estrogen, 17β-estradiol (E2). P4 generally supports implantation, whereas minute elevations of E2 terminate it. Diverse maternal stressors can cause implantation to fail, usually by raising the female’s endogenous E2:P4 ratio. This is viewed as an ancient mammalian adaptation that forestalls adverse outcomes when circumstances are not propitious to maternal and fetal/offspring health.

In 1959, it was discovered that exposing inseminated female mice to novel males (those other than the sire) caused implantation failure (the Bruce effect). Novel males of a genetic strain distinct from the sire’s strain induced the strongest effects. This led to the notion that the inseminated female imprints on the sire’s odor and reacts differently to novel males’ odors (the olfactory memory hypothesis). Females experiencing the Bruce effect showed degeneration of the ovarian corpora lutea, which produce P4 and are normally sustained by pituitary prolactin pulses. The effect was shown to be mitigated by rendering the female anosmic or by giving her exogenous prolactin or P4. This led to decades of research examining constituents of male urine that signal individual differences, receptors in the olfactory system that transduce chemical messages to neural signals, and neural pathways that bring this information to the hypothalamus, which controls pituitary prolactin. Unfortunately, much of this research was conducted without reference to the phenomenon of stress-induced implantation failures, and some of it was confounded by human handling and other stress-inducing procedures.

Later, it was discovered that male urine and seminal emissions contain substantial quantities of bioactive E2, especially when males have not recently mated and are near females. Manipulations that diminish male urinary E2 and those that reduce female reactivity to E2 can prevent the Bruce effect. When tritium-labeled E2 (³H-E2) is administered to males, untreated females housed briefly with these males show substantial radioactivity in the uterus and other tissues where estrogen receptors are abundant. This steroid transfer occurs without mediation by the brain, as E2 is a small, polar, and lipophilic molecule that is readily absorbed percutaneously, nasally, and vaginally directly into circulation. Moreover, when novel males are housed directly with females and allowed to mate, relatively high levels of E2 are deposited directly into the female’s reproductive tract.

The olfactory memory and the male-sourced-E2 hypotheses are not mutually exclusive alternatives. In fact, they are complementary, as a high E2:P4 ratio impedes implantation via several known uterine mechanisms. Just as there are multiple and often redundant mechanisms that subserve other fundamental adaptations (e.g., hunger, thirst, mating behavior, and circadian rhythm), the Bruce effect is multicausal.