Obstetrics and Gynaecology - Theses

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    Human chorionic gonadotrophin: the clinical and physiological role of LCG heterogeneity
    Hay, David Lachlan ( 1986)
    This thesis considers the heterogeneity of human chorionic gonadotrophin (hCG) in vivo. This was studied in terms of the presence of free alpha hCG subunit, free beta hCG subunit, and metabolites, which accompany dimer hCG secretion in both pregnancy and malignancy. Also, the microheterogeneity of hCG arising from variations in its carbohydrate content was studied to establish whether it changes systematically during pregnancy or in malignancy. The use of highly specific monoclonal antibodies enabled hCG, its free subunits, and metabolites, to be accurately monitored in maternal serum and urine samples, both from the earliest stages of blastocyst implantations until delivery, and in trophoblastic and non-gestational malignancy. These profiles were confirmed by gel chromatography. The changes in hCG heterogeneity were also correlated with a detailed immunohistochemical study of placental tissue. From these studies it was possible to develop a proposal for the physiological mechanisms regulating hCG production. It is proposed that hCG synthesis is regulated through the differentiation of cytotrophoblasts into syncytiotrophoblasts. The mechanism of control involves limited translation of the genes for alpha and beta hCG subunits in cytotrophoblasts and in differentiating intermediate cells. Translation of the hCG genes ceases following the fusion of differentiating cytotrophoblasts into syncytiotrophoblasts, and the cellular machinery of syncytiotrophoblasts transcribes messenger RNA (mRNA) accumulated during differentiation. Thus, the total concentration and relative balances of mRNA for the hCG subunits in syncytiotrophoblasts are dependent on the rate and number of differentiating cytotrophoblasts. This proposal enabled the production of hCG and its subunits to be correlated with the changing histology of the placenta in pregnancy, and with unusual histological changes occurring in malignancy. The clinical role of hCG heterogeneity was investigated. Although dimer hCG was the predominant species secreted in pregnancy and malignancy, hCG heterogeneity provided information about both complications of pregnancy and malignancy. Examples of this included the following: increased free beta subunit to hCG ratios in early pregnancy in patients with subclinical abortions or abnormal pregnancies; increased levels of urinary immunoreactive hCG fragments in pre-eclamptic patients with renal complications; increased ratio of free beta subunit to hCG in patients with previous trophoblastic disease, signalling the proliferation of potentially malignant cell lines. The use of chromofocusing columns in HPLC enabled the changes in hCG microheterogeneity to be evaluated at different stages of pregnancy and malignancy. These studies demonstrated a decrease in the number of hCG microvariants with increasing gestation, that the average distribution of hCG microvariants became more basic with increasing gestation, and the release of partially glycosylated intermediates in malignancy. Preliminary studies on the fate of hCG microvariants in rats demonstrated that the origin of hCG microheterogeneity was in its synthesis rather than in the metabolism of a single microvariant. It was proposed that the factors regulating hCG glycosylation included the changing histology of trophoblastic villi and subsequent changing of the relative positions of glycosylating enzymes, and the modification by steroids of the activity of sialyl transferase. It was proposed that hCG activity is regulated at two levels. The primary control is regulation of circulating concentration, which is effected by changes in placental histology, and the secondary control is on biological emphasis, mediated through the carbohydrate moiety. This enables the placenta to synthesize a multifunctional hormone, and to shift its biological emphasis and activity during different stages of pregnancy.