DEVELOPMENT OF HUMAN PRIMORDIAL FOLLICLES TO ANTRAL STAGES IN SCID HPG MICE STIMULATED WITH FOLLICLE-STIMULATING-HORMONE/

In contrast to the many detailed studies of Graafian follicles, the bi ology of small follicles in the human ovary is poorly understood and t he trigger for follicular growth initiation remains unknown. No practi cal model exists to study preantral follicle growth in the human becau se of their slow growth rate and lack of an effective culture system. We therefore tested ovarian xenografts as a new strategy to study the early stages of ovarian follicular growth in vivo. Mice homozygous for severe combined immunodeficiency (SCID) and hypogonadism (hpg) receiv ed human ovarian xenografts under their kidney capsules. Follicle grow th aas assessed by morphology and proliferating cell nuclear antigen ( PCNA) immunostaining. The grafts were recovered after 11 (short-term) and 17 weeks (long-term), and serially sectioned, During the last 6 we eks of long-term grafting, mice were randomized to receive either plac ebo or 1 IU of purified follicle stimulating hormone (FSH) s.c. on alt ernating days. After 11 weeks of grafting, the most advanced follicles had a maximum of two granulosa cell layers. In the absence of FSH adm inistration, follicles did,not progress beyond the two-layer stage eve n after 17 weeks of grafting, and the oestradiol levels remained undet ectable, In the FSH-treated long-term grafts, follicles had grown to a ntral stages and resulted in oestradiol levels as high as 2070 pmol/l, Growth initiation indices did not differ between control and FSH-trea ted grafts. This study demonstrates that follicles can survive and gro w in human ovarian tissue grafted under the renal capsules of immunode ficient mice for at least 17 weeks, and indicate that xenograft models are potentially useful for studying human follicle development. Using this physiological model, we showed that FSH is required for follicle growth beyond the two-layer stage, although growth initiation is inde pendent of gonadotrophin stimulation.