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The sympathomimetic drugs noradrenaline, methoxamine, tyramine and norephedrine, caused rhythmic contractions in isolated human vasa deferentia. These contractions were mediated via α-adrenorcceptors. Intravenous administration of some of these drugs into rats and guinea-pigs produced contractions of the vas deferens in vivo but was accompanied by severe cardiovascuiar side effects. Hence a local method of application, using medical grade silastic in the form of collars or rods was developed. Insertion of fhese slow-releasing devices around the vas deferens in anaesthetized rats produced rhythmic contractions without serious side effects. In a fertility screen, these silastic drug mixtures caused a temporary reduction in fertility of male rats and rabbits. The maximal antifertility action occurred in the first week foIlowing the insertion of drug-containing collars or rods. At the time of the peak effect on fertility, the numbers of sperm in the ejaculate were reduced to almost zero. In addition the treatment impaired the quaIity of the ejaculated sperm. Spontaneous restoration of fertiIity was evident with some of the treatments, but not with others. It was concluded that the main cause of infertilty was the reduction of sperm numbers in the ejaculate resulting from either a block in sperm transport in the vas deferens or by a deficiency in the mechanism of emission. An occlusion of the vas may result from a mechanical block as with methoxamine or from a sustained spasm. A defect in emission may result from depletion of the transmitter, receptor-specific desensitization or by pre-synaptic α-receptor mediated inhibition.

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Unlike humans, the primary signal for maternal recognition ofpregnancy in ruminants is the Type I interferon (IFN) IFN-t. IFN1: is produced by the conceptus and acts upon the endometrium where it inhibits the production ofprostaglandin F2a and subsequent luteolysis ofthe corpus luteum. It is difficult to establish what precise role interferonlike signalling might play in human reproduction due to ethical barriers. However, indirect investigations are possible by in vitro investigation . of human endometrial . response to Type I IFN stimulation. Type I IFNs (a, P and 1:) activate a common tyrosine kinase signalling pathway' involving the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins. However, the Type I IFNs elicit different cellular responses. The aim of this thesis is to establish that, whilst it is known that the Type I IFNs trigger~e JAKISTAT activation pathway, there is a simultaneous activation of different phospholipase pathways which determines the specificity of the response. This hypothesis was investigated using human endometrial tissue which is known to respond to Type I IFNs. Long-term primary human endometrial cell cultures were established from tissue taken from the proliferative and secretory phases of the menstrual cycle. Cell function and viability were determined by measuring placental proteins and cytokines. 33p labelled endometrial cells exposed to IFNs a and 1: showed hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) with corresponding production of diacylglycerol (DAG). IFNa and IFN1: also stimulated hydrolysis of phosphatidylinositol-4- phosphate (pIP). These IFNs did not demonstrate activation of any other phospholipase. There was no phospholipid turnover via any phospholipase in response to IFN~. Using imrnunoprecipitation, SDS-PAGE and Western blotting it was possible to show the presence of phosphorylated STATl a in unstimulated endometrial cells. In response to stimulation by IFN a and ~ there was an increase in phosphorylated STATla, STATI and Tyk2 (a member ofthe Janus kinase family). In contrast, IFN1: activated the phosphorylation of Tyk2 but not STATla or STATI. There was no stimulation of JAKl phosphorylation by any of the IFNs. In summary, Type I IFNs u, ~ and 1: each elicit a different pattern of signal transduction response in cultured human endometrial cells, not only via the JAKISTAT pathway but also via phospholipase activation. The ability of IFN't to stimulate a signalling pathway, distinct from that of IFNu and ~ is sufficient circumstantial evidence to suggest that at least a residual signalling pathway for IFN't exists in the human endometrium and further investigation is warranted.

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