The pros and cons of phytoestrogens

Abstract

Phytoestrogens are plant derived compounds found in a wide variety of foods, most notably soy. A litany of health benefits including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms, are frequently attributed to phytoestrogens but many are also considered endocrine disruptors, indicating that they have the potential to cause adverse health effects as well. Consequently, the question of whether or not phytoestrogens are beneficial or harmful to human health remains unresolved. The answer is likely complex and may depend on age, health status, and even the presence or absence of specific gut microflora. Clarity on this issue is needed because global consumption is rapidly increasing. Phytoestrogens are present in numerous dietary supplements and widely marketed as a natural alternative to estrogen replacement therapy. Soy infant formula now constitutes up to a third of the US market, and soy protein is now added to many processed foods. As weak estrogen agonists/antagonists with molecular and cellular properties similar to synthetic endocrine disruptors such as Bisphenol A (BPA), the phytoestrogens provide a useful model to comprehensively investigate the biological impact of endocrine disruptors in general. This review weighs the evidence for and against the purported health benefits and adverse effects of phytoestrogens.

Fig. 1

Summary of the pros and cons of genistein. The illustration depicts the rat hypothalamic–pituitary–gonadal (HPG) axis, indicating key components (in red) known to be vulnerable to disruption by genistein administration during critical windows of development. Developmental exposure to genistein can also result in abnormal development of the accessory sex glands (blue). Artwork by Barbara Aulicino. Edited and reprinted by permission of American Scientist, magazine of Sigma Xi, The Scientific Research Society.

Fig. 2

During the neonatal period, estrogen (E2), aromatized from testicular testosterone (T), defeminizes the male rodent brain such that a GnRH surge cannot be elicited by steroid positive feedback. If E2 action is blocked, by castration, inhibition of aromatase, or disruption by endocrine disruptors, then the female GnRH pattern results. In females, the ovaries are quiescent at birth. Thus, the female-typical GnRH secretion pattern develops in the absence of E2. The administration of E2 during this critical period produces the male pattern, and the loss of the preovulatory GnRH surge. We have found that administration of 10 mg/kg genistein to neonatal females in abrogated GnRH activation by steroid hormones, an effect which is consistent with defeminization.

Fig. 3

Summary of the disruptive effects of neonatal genistein or equol exposure in the female rat HPG axis. (A) Day of vaginal opening (a hallmark of puberty in the rat) is advanced in female rats neonatally exposed to estradiol benzoate (EB) or genistein (GEN) but not equol (EQ) during the first 4 days of life compared to vehicle treated controls (OIL). (B) By 15 weeks of age only 29% of GEN and 25% of EQ exposed animals displayed a regular estrous cycle compared to 100% of the control animals and none of the EB treated animals. (C) Immunolabeling of GnRH (red) and Fos (green) was used as an indicator of GnRH activation following hormone priming. The percentage of GnRH neurons immunopositive for Fos was significantly lower in the animals neonatally exposed to GEN or EQ indicating that both defeminized steroid positive feedback signaling pathways. (D) The density of neuronal fibers immunopositive for kisspeptin (KISS, red) surrounding GnRH neurons (green) was significantly lower in animals neonatally treated with EB or GEN but not EQ. Reduced stimulation of GnRH by kisspeptin neurons may be a mechanism by which GnRH activity is impaired in females exposed to GEN and possibly other isoflavones during development. (Means ± SEM, *p ≤ 0.05.)

Fig. 4

Implantation sites following transfer of control blastocysts into control and genistein-treated recipient mice. (A) Uterus of a control mouse 8 days after transfer of control blastocysts (4 normal implantation sites). (B) Uterus of a genistein-treated mouse 8 days after transfer of control blastocysts (no implantation sites visible).