Reproductive and gonadal function in the female after therapy for childhood malignancy.
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Biomedical subjects
Publications and source records attributed to R J Stillman.
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The frequency and causes of ovarian failure among 182 long-term survivors of childhood cancer were examined. Twenty-two patients (12%) had ovarian failure. Ovarian failure was found in 17 of 25 patients (68%) who had both ovaries within abdominal radiotherapy fields, in five of 35 patients (14%) whose ovaries were at the edge of the treatment field, and in none of 122 patients with one or both ovaries outside of an abdominal treatment field (p < 10(-4)). The odds for ovarian failure in patients with both ovaries in the field are 19.7 higher than those for other irradiated patients (95% confidence interval, 5.3 to 72.8). Covariate and multivariate analyses of tumor type, age at diagnosis, duration of follow-up, abdominal tumor surgery, abdominal radiotherapy, number of chemotherapeutic agents administered, and cumulative doses of several drugs revealed that the location of the ovaries relative to radiation treatment fields was the only risk factor for subsequent ovarian failure.
Glucocorticoids accelerate fetal lung maturation in all mammals studied, and in some species, such as goat and sheep, concentrations of fetal cortisol increase sharply before term, bringing about a train of events leading to parturition. Studies of cortisol in the umbilical cord blood have revealed no such increase at the end of human pregnancy. But information obtained in that way is difficult to interpret because much of the fetal cortisol is of maternal origin and its concentration, if sampled at delivery, is affected by maternal stress. These problems can be avoided to some extent by studying other fetal corticoids. Corticosterone sulphate (once called compound B, and abbreviated to BS) is produced by fetal adrenal glands and is present in greater concentrations in human fetal plasma than in maternal plasma. It is hydrolysed by the placental sulphatases and is a poor substrate for for placental 11 beta- hydroxysteroid dehydrogenase. We report here confirmation that the bulk of maternal BS originates from the fetus, and that its concentration increases suddenly at term.
The effects of danazol on steroidogenesis in vitro in the 16-20 week old human fetal adrenal were examined by studying: 1) danazol binding to adrenal microsomal and mitochondrial cytochrome P-450, and 2) enzyme kinetics of danazol inhibition of the adrenal microsomal 21-hydroxylase and the mitochondrial 11 beta-hydroxylase. The addition of danazol to preparations of adrenal microsomes or mitochondria elicited a type I cytochrome P-450 binding spectrum. Danazol bound to microsomal cytochrome P-450 binding spectrum. Danazol bound to microsomal cytochrome P-450 with a high affinity apparent spectral dissociation constant (KS) of 1 microM and with a lower affinity K's of 10 microM. Danazol bound to mitochondrial cytochrome P-450 with a KS of 5 microM. In addition, danazol competitively inhibited the microsomal 21-hydroxylase (apparent enzymatic inhibition constant KI = 0.8 microM) and the mitochondrial 11 beta-hydroxylase (KI = 3 microM). These findings demonstrate that low concentrations of danazol directly inhibit steroidogenesis in the human fetal adrenal in vitro.
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Normal cyclic menstruation involves a delicate concert of hormonal events, characterized by midcycle ovulation and, if no pregnancy is achieved, menstrual flow. Women's health--and especially their reproductive health and fertility--may be affected by abnormalities in cyclicity or in menstruation. A number of valuable modes of therapy have recently become available. Abnormal cyclicity may be caused by decreased estrogen levels (from exercise, smoking, or eating disorders). Small ovulation induction pumps, which deliver minute physiologic concentrations of gonadotropin-releasing hormone (GnRH) around the clock, can be used for safe and successful treatment. Increased estrogen levels may also affect cyclicity, and may be suppressed with new GnRH antagonists or stimulated to cyclicity with pure follicle-stimulating hormone. Abnormal menstruation may be caused by intrauterine scarring or fibroids. Outpatient hysteroscopic surgery may successfully and conservatively be used to treat these problems. Today, even women who have been born without a uterus or who have undergone hysterectomy may have a child through a host uterus program. This combines in vitro fertilization of the husband's sperm with his wife's egg with transfer of the embryo into a host who is capable of carrying the pregnancy. Our potential to improve women's reproductive health continues to expand, as some of the recent developments described above for treating abnormalities of cyclicity or menstruation attest.