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 biologyof small follicles in the human ovary is poorly understood and the triggerfor follicular growth initiation remains unknown. No practical model existsto study preantral follicle growth in the human because of their slowgrowth rate and lack of an effective culture system. We therefore testedovarian xenografts as a new strategy to study the early stages of ovarianfollicular growth in vivo. Mice homozygous for severe combinedimmunodeficiency (SCID) and hypogonadism (hpg) received human ovarianxenografts under their kidney capsules. Follicle growth was assessed bymorphology 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 weeks of long-term grafting, micewere randomized to receive either placebo or 1 IU of purified folliclestimulating hormone (FSH) s.c. on alternating days. After 11 weeks ofgrafting, the most advanced follicles had a maximum of two granulosa celllayers. In the absence of FSH administration, follicles did not progressbeyond the two-layer stage even after 17 weeks of grafting, and theoestradiol levels remained undetectable. In the FSH-treated long-termgrafts, follicles had grown to antral stages and resulted in oestradiollevels as high as 2070 pmol/l. Growth initiation indices did not differbetween control and FSH-treated grafts. This study demonstrates thatfollicles can survive and grow in human ovarian tissue grafted under therenal capsules of immunodeficient mice for at least 17 weeks, and indicatethat xenograft models are potentially useful for studying human follicledevelopment. Using this physiological model, we showed that FSH is requiredfor follicle growth beyond the two-layer stage, although growth initiationis independent of gonadotrophin stimulation.