Therapeutic Interventions into Early Stages of Follicle Maturation: A New Treatment Paradigm After Over 50 Years of Modern Infertility Therapy (2013)

A study by Mahran et al in this issue of the journal suggests that tamoxifen cotreatment in rats to a large degree negates radiotherapy-induced loss of follicles in female Sprague-Dawley rats (1). As they note, this observation has been made before (2), but Mahran et al are the first to suggest mechanisms by which tamoxifen achieves these effects. By suggesting that tamoxifen ameliorates the deleterious effects of irradiation on oxidative stress and apoptosis via IGF-I-mediated processes, they offer a link to previously noted androgen data (3) and to a recently evolving new treatment paradigm in female infertility, expanding therapeutic interventions from the last 2 weeks, the gonadotropin-sensitive stage, to earlier stages of follicle maturation (4). The modern age of fertility therapy dawned in the midto-late 1950s when Lunenfeld (5, 6) and Gemzell (7, 8) laid the groundwork for gonadotropin therapy. Ever since, the treatment of female infertility has centered on the gonadotropin-dependent stage of follicle maturation, which encompasses only the last 14 days of an, otherwise, monthslong process (4, 9). Despite increasing evidence that oogonial stem cells exist in mammalian ovaries (10, 11), current dogma still holds that, at minimum, a large majority of unrecruited (resting) primordial follicles are created during early embryonic life, when follicle numbers peak (Figure 1). Active recruitment after menarche transfers a steady stream of resting into growing follicles, advancing them through primary, secondary, and preantral follicle stages, before becoming sensitive to FSH at antral stages (12). Granulosa cells of only small growing follicles are characterized by steadily increasing androgen receptors, and their knockout severely disrupts normal follicle growth, reproducing fairly typical human infertility diagnoses (13). Androgen supplementation in women with androgen deficiency, especially encountered with low ovarian reserve (14), has, therefore, become the first widely practiced infertility treatment affecting early stages of follicle maturation in over 50 years of modern infertility practice (15). Involving oxidative stress, and apoptotic as well as proliferative activities, chemoand radiotherapy can damage follicles in different ways. To minimize such iatrogenic damage, various strategies and agents have been proposed (16–18). Mahran et al now add to our understanding of how one of these agents, tamoxifen, appears to desensitize female rat ovaries from radiation effects via IGF-I-mediated processes (1). This is a potentially important observation, because IGF-I effects at small growing follicle stages are well documented in a variety of animal models (19–21) and in humans (22). IGF-I also plays a significant role in the induction of steroidogenic enzyme genes in the human adrenal cortex, affecting adrenal hormone production (23). IGF-I (and IGF-II) predominantly stimulates androgen biosynthesis via the IGF-I receptor (24, 25). Androgens, in turn, as noted above, enhance normal follicle growth at small growing follicle stages immediately after recruitment (4). Whether effects described by Mahran et al (1) represent direct IGF-I effects or are secondarily mediated