Control of vascular reactivity in pregnancy.

Human pregnancy is characterized by a blunted pressor responsiveness to vasopressor substances. This was first reported by Dieckmann and Michel in 1937 in experiments in which they measured vascular reactivity to the pressor effects of a crude preparation of vasopressin. Recently, this has been reported to occur in response to epinephrine, norepinephrine (NE), and angiotensin II (AII). Gant and associates reported that the increasing vascular sensitivity to infused AII not only was characteristic of women who developed pregnancy-induced hypertension, but in fact preceded the development of pregnancy-induced hypertension. Although a variety of factors may mediate this blunted pressor responsiveness, the most likely candidate appears to be the localized production within endothelium and/or vascular smooth muscle of prostaglandins. Indeed, administration of indomethacin or aspirin results in an increased sensitivity to infused AII in normotensive previously AII-refractory women. Administration of the steroid hormone 5 alpha-dihydroprogesterone reverses this apparent prostaglandin-mediated response. In addition, administration of the phosphodiesterase inhibitor, theophylline, results in a restoration of vascular refractoriness to infused AII in women with pregnancy-induced hypertension or in women destined to develop pregnancy-induced hypertension. Although a variety of known and possibly unknown compounds might also effect the control of vascular reactivity during human pregnancy, the prostinoids appear to play a pivotal role in mediation of control of vascular reactivity during human pregnancy.

Dysfunctional uterine bleeding. Clarifying its definition, mechanisms, and management.

"Dysfunctional uterine bleeding" is not a generic term for abnormal uterine bleeding. Rather, it refers solely to bleeding caused by an ovarian endocrinopathy. Estrogen withdrawal and inappropriately sustained estrogen production are the two mechanisms responsible. The latter mechanism produces estrogen breakthrough bleeding, which is common in women with chronic anovulation. Treatment of estrogen withdrawal bleeding depends on when in the menstrual cycle bleeding occurs. Anovulatory bleeding is best treated with progestin. Estrogen therapy is contraindicated, except in patients with profuse anovulatory bleeding unresponsive to progestin treatment, because it increases the risk of endometrial hyperplasia and cancer.

Adrenal corticoid hyperresponsiveness in hirsute women.

Data are limited on the existence of adrenal hyperplasia or cortisol oversecretion in women with hirsutism. Supranormal responses of cortisol (greater than 20 micrograms/dl) were observed at 15 and 30 minutes after the 8:00 A.M. adrenocorticotropin (0.5 U) injection (performed after 1 mg of dexamethasone taken orally at midnight) in 6 of the 12 hirsute women (hirsute I) and in all 4 women with Cushing's disease. Baseline plasma levels of corticoids, androgens, and gonadotropins, body weight, menstrual history, and degree of hirsutism were all indistinguishable between the two hirsute groups. The mean plasma levels of cortisol and 17-hydroxyprogesterone were both significantly greater in the hirsute I group and in those with adrenal hyperplasia caused by Cushing's disease than in normal subjects. Our data indicate that adrenal hyperplasia is a common abnormality in women with hirsutism. We speculate that this abnormality may contribute to the pathogenesis of hirsutism and ovarian dysfunction in many hirsute women.

Extraadrenal steroid 21-hydroxylase activity in a woman with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency.

The 21-hydroxylation of plasma progesterone (P) has been demonstrated in pregnant, nonpregnant, and adrenalectomized women and in men. The fractional conversion of plasma progesterone to deoxycorticosterone (DOC), [rho]P-DOC BU, among those subjects was 0.009 +/- 0.001 (mean +/- SEM, n = 32). The [rho]P-DOC BU in a woman with congenital adrenal hyperplasia due to apparent adrenal steroid 21-hydroxylase deficiency was 0.010 when she was taking cortisone acetate, and the [rho]P-DOC BU determined when she was not taking cortisone acetate was 0.012. Moreover, the value computed for the fractional conversion of 17 alpha-hydroxyprogesterone to 11-deoxycortisol in this woman (0.004) was similar to that observed in a woman with normal adrenal function (0.005). Therefore, extraadrenal 21-hydroxylase activity in a woman with nonsalt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency was similar to that found in persons with normal adrenal function.

Effect of pregnancy on diabetic retinopathy.

The incidence of progression of diabetic retinopathy during pregnancy is unknown and its proper management uncertain. In this study, 55 insulin-dependent diabetic patients under strict glucose control were followed throughout pregnancy with serial retinal examinations by ophthalmoscopy and photographs. Nineteen patients had minimal or background retinopathy and 7 had untreated proliferative changes. Six patients had been treated before pregnancy with photocoagulation for proliferative retinopathy. A positive correlation was found between progressive proliferative diabetic retinopathy and the duration of diabetes mellitus independent of glucose control. During gestation 3 of 19 patients (16%) with minimal or background retinopathy and 6 of 7 patients (86%) with untreated proliferative retinopathy experienced deterioration of their eye disease. In 4 patients with proliferative retinopathy, progression of retinal disease was arrested with photocoagulation during pregnancy. Only 1 of 6 who had received laser treatment prior to pregnancy experienced progression of her retinopathy. These results suggest that photocoagulation prior to pregnancy may protect against rapidly progressive proliferative retinopathy and that aggressive treatment during pregnancy can prevent progression of proliferative retinopathy and visual impairment.

Age, estrogen, and bone density.

Osteoporosis in hypogonadal women contributes to considerable morbidity, mortality, and health care expense in our country each year. Estrogen deficiency accelerates and increases the incidence of this problem, and estrogen replacement therapy can substantially retard, and may in fact forestall, abnormally rapid loss of bone mineral mass in aging women. Moreover, estrogen therapy probably substantially decreases the incidence of disabling fractures in elderly women. These potential benefits of estrogen therapy in women at high risk to develop osteoporosis probably outweigh the risks of such a regimen, especially when a progestin is added for the last several days of each estrogen cycle. Optimal diet and suitably vigorous physical activity are advisable for all women as they enter the postmenopausal phase of their lives. Calcium supplementation, estrogen replacement therapy, or both are recommended when the patient is at high risk to develop osteoporosis.

Control of vascular responsiveness during human pregnancy.

Normal human pregnancy is characterized by vascular refractoriness to AII. This pregnancy-induced vascular refractoriness appears to be mediated principally by decreased vascular smooth muscle responsiveness to AII rather than by alterations in blood volume or plasma concentrations of renin or AII. The mechanism that controls vascular refractoriness during normal pregnancy likely involves a localized prostaglandin or prostaglandin-like action mediated through cyclic nucleotides. The action of progesterone or one of its metabolites appears to mediate the synthesis or the catabolism of locally produced prostaglandins or prostaglandin-like agents.

Oral administration of theophylline to modify pressor responsiveness to angiotensin II in women with pregnancy-induced hypertension.

Normally, women become refractory to the pressor effects of infused angiotensin-II (A-II) early in pregnancy. Gravid women destined to develop pregnancy-induced hypertension (PIH) lose this refractoriness to A-II several weeks prior to the detection of hypertension. Normal pregnant women also lose their A-II refractoriness after treatment with prostaglandin synthetase inhibitors and, in this regard become similar to gravid women who are destined to develop PIH. From this observation, we have concluded that a prostaglandin(s) or a prostaglandin-related substance(s) is likely involved in the mediation of vascular reactivity to A-II during pregnancy. The present study was conducted to ascertain if control of vascular reactivity during pregnancy also involves the cyclic nucleotides. Since theophylline is known to inhibit the action of phosphodiesterase, an action that results in increased cellular levels of cyclic 3',5'-adenosine monophosphate (cAMP), we evaluated the effective pressor dose of A-II before and after the administration of theophylline to women with mild PIH who were beyond the 28th week of gestation. The effective pressor dose of A-II in these women with PIH before theophylline treatment was 7.3 +/- 1.4 ng. times kg.(-1) times min.(-1) (mean and standard error). Following treatment of these women with the equivalent of 500 mg. of theophylline daily for four days, the effective pressor dose of A-II was 16.7 +/- 3.8 ng. times kg.(-1) times min.(-1) (p less than 0.025). These findings are consistent with the view that a prostaglandin(s) synthesized in the arteriole may modulate the vascular refractoriness to A-II by altering the intracellular level of cAMP in vascular tissues.

Effect of prostaglandin synthetase inhibitors on pressor response to angiotensin II in human pregnancy.

Pregnant women destined to develop pregnancy-induced hypertension (PIH) lose refractoriness to the pressor effects of infused angiotensin II (A-II) several weeks before the onset of hypertension. This loss of refractoriness to A-II is unrelated to plasma renin activity or circulating levels of A-II. In animal studies it has been shown that the prostaglandins are important mediators of vascular reactivity. Specifically, the uterine blood flow appears to vary directly with prostaglandin E concentrations in uterine venous effluent. The present study was designed to evaluate the effects of prostaglandin synthetase inhibitors on the pressor effects of A-II in human pregnancy. The "effective A-II pressor dose" (nanograms of A-II X kg-1 X min-1 necessary to cause a 20 mm Hg rise in diastolic pressure) was determined in 14 pregnant women before and after treatment with either 25 mg indomethacin or 600 mg aspirin given twice, 6 h apart. The effective pressor dose required before treatment [22.7 +/- 3.4 ng X kg-1 X min-1 (mean +/- SE)] was significantly greater than that after treatment [8.7 +/- 1.2 ng X kg-1 X min-1 (P less than 0.001)]. The refractoriness to A-II observed in normal human pregnancy may be mediated in part by the action of prostaglandins or related substances produced in the arteriole.

Modification of vascular responsiveness to angiotensin II in pregnant women by intravenously infused 5alpha-dihydroprogesterone.

In gravid women who are destined to develop pregnancy-induced hypertension (PIH), normal pregnancy-associated refractoriness to the pressor effects of administered angiotensin II (A-II) is lost several weeks before the onset of hypertension. From a study of the determinants of A-II pressor responsiveness in normal gravid women, it appears likely that the loss of resistance to A-II is principally unrelated to plasma renin activity or to plasma A-II levels. However, it recently has been shown that the vascular refractoriness to A-II in normal women can be reduced significantly by the administration of the prostaglandin synthetase inhibitors, indomethacin or aspirin. In seven women who had developed PIH and who had lost their refractoriness to A-II, the infusion of 5alpha-pregnan-3,20-dione (5alpha-DHP) was associated with restoration of refractoriness to the pressor effects of A-II. Moreover, in five normotensive gravid women beyond 28 weeks' gestation in whom the refractoriness to A-II was reduced by the administration of indomethacin, the intravenous infusion of 5alpha-DPH was associated with restoration of refractoriness to the pressor effects of A-II. These observations are consistent with the view that a progesterone metabolite(s) may be important in the maintenance of normal blood pressure during human pregnancy.