Female sterility resulting from oocyte destruction is an unfortunate, and in many cases inevitable, consequence of chemotherapy. We show that unfertilized mouse oocytes exposed to therapeutic levels of the antitumor drug, doxorubicin (DXR), undergo apoptosis; however, fertilized oocytes do not initiate apoptosis, but enter cell-cycle arrest, when treated with DXR. Apoptosis induced by DXR in oocytes is blocked by sphingosine-1-phosphate, an inhibitor of ceramide-promoted cell death. Oocytes from Bax-deficient, but not p53-null, female mice display complete resistance to DXR-induced apoptosis in vivo and in vitro. Pretreatment of oocytes with a specific peptide inhibitor of caspases also abrogates the apoptotic response to DXR. These findings indicate that oocyte destruction caused by chemotherapy can be prevented by manipulation of apoptosis-associated signaling pathways.

Inhibin, activin, and follistatin (FS) are gonadal proteins that appear to have a role in regulating folliculogenesis through possible paracrine and/or autocrine interactions. To further examine the potential role of activin in oocyte-granulosa cell communication, we developed a sensitive reverse transcription-polymerase chain reaction protocol to analyze mRNA for the alpha, betaA, and betaB inhibin/activin subunits, FS, and the four activin receptor subtypes in individual human and mouse oocytes. The resulting expression pattern was further compared to that in human cumulus granulosa cells. Our results indicate that neither ssA nor betaB mRNA was detectable in any human or mouse oocyte, that alpha subunit was marginally present in some of the human oocytes, and that FS mRNA was detectable in human but not mouse oocytes. On the other hand, inhibin/activin subunit and FS mRNAs were abundantly expressed in cumulus cells. In addition, mRNAs for all four activin receptor subtypes (ActRIA, ActRIB, ActRIIA, and ActRIIB) were easily detectable in both oocytes and granulosa cells and appeared to be differentially expressed in oocytes during nuclear maturation. Finally, RNAs for both zona pellucida 3 and growth-differentiation factor-9, which were originally used as oocyte-specific markers, were detected in human but not mouse cumulus cells, although at lower levels than observed in oocytes. Taken together with previous studies, these results indicate that oocytes may be capable of responding to, but not synthesizing, activin.

A case series of eight cycles of in-vitro fertilization (IVF) in five women diagnosed with malignant disorders is presented. These patients chose to defer definitive treatment for a chance for preservation of potential fertility. The response of these patients to ovarian stimulation, and the outcome, was compared with 17 IVF cycles in 12 age-matched patients with isolated tubal infertility. An apparent adverse influence of malignant disease on the quality and behaviour of oocytes was observed. Despite a comparable total number of oocytes per cycle in the two groups, a significantly reduced percentage of mature oocytes was retrieved per cycle from patients with malignant diseases. The oocytes from patients with malignant disorders were of a poorer quality and exhibited a significantly impaired fertilization rate compared to the controls. We propose that neoplastic processes, irrespective of the site or cell of origin, may have a detrimental impact on the biology of oocytes, an effect akin to that seen on spermatozoa in men with certain malignancies.

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