Lee A. Rigg

Pattern of increase in circulating prolactin levels during human gestation

Serum prolactin concentrations, determined serially at weekly intervals from the fifth week of gestation, increase in an approximately linear pattern. It is suggested that in human gestation the increase in prolactin secretion is related to supramaximal estrogen augmentation at all times and is a functional reflection of hypertrophy and hyperplasia of pituitary lactotrophs.

The 24-hour excursion and diurnal rhythm of glucose, insulin, and C-peptide in normal pregnancy☆☆☆

Abstract A longitudinal study to quantitate the progressive effects of the second and third trimesters of normal pregnancy on the levels of plasma glucose, immunoreactive insulin (IRI), and C-peptide (C-P) at hourly intervals throughout the 24-hour “metabolic clock” was made. Identical studies were conducted in each subject at 6 to 11 weeks post partum and these data were used as nonpregnant control values. Data analyses were made to determine the role of meal-activity-sleep cycles as physiologic modifiers. A diurnal rhythm of plasma glucose, IRI, and C-P was demonstrated in all study periods. During meals anabolic values of plasma glucose (increments above the 24-hour mean) in response to meal intake were remarkably small, ranging between 30 and 35 mg/100 ml in the postpartum state, and were not significantly modified by pregnancy. The corresponding IRI levels were similarly small with a mean increase on only 31% in pregnancy. However, during the third but not the second trimester of pregnancy, the peak anabolic values for both plasma glucose and IRI were significantly (p a.m. ) plasma glucose and 24-hour integrated glucose levels. This relative nocturnal hypoglycemia was associated with synchronous IRI values but without concomitant reduction of absolute IRI levels. Consequently, the fasting, premeal, and 24-hour IRI/glucose ratios were increased. Thus, basal insulin secretion is significantly augmented relative to levels of plasma glucose, but a quantitative increase in insulin secretion following food intake is relatively small during pregnancy. These observations together with the finding of a marked diurnal rhythm of plasma glucose and relative nocturnal hypoglycemia provide important insights for the formulation of guidelines for the timing, amount, and mode of delivery of exogenous insulin necessary for the management of diabetic patients during pregnancy.

Qualitative and quantitative assessment of the circadian rhythm of cortisol in pregnancy.

The effect of pregnancy on the circadian rhythm and diurnal excursion of plasma cortisol and urinary free corticoids was examined in a sequential study during the second and third trimester and 6 to 12 weeks post partum. Hourly blood samples from six subjects and 8-hour urine collections from eight subjects were obtained around the clock. While the circadian rhythm was maintained during gestation, plasma cortisol levels (24-hour mean, nadir, peak, and nadir-peak excursion) increased. The relative excursion of plasma cortisol (expressed as the percentage of deviation from the 24-hour mean) exhibited remarkable blunting compared with postpartum values. This pregnancy-associated blunting of plasma cortisol excursion was indicated by a significant reduction in the: (1) mean peak and nadir excursion, (2) integrated area between the percent deviation curve and the 24-hour mean, and (3) mean slope of the major incremental and decremental segments of the percent deviation curve. The circadian rhythm and diurnal excursion of plasma cortisol were reflected in urinary free corticoid values. Mean 24-hour urinary free corticoid concentrations increased 180% during gestation over nonpregnant levels. Nadir concentrations of urinary free corticoids in pregnancy exceeded peak nonpregnant levels. The gestational rise of metabolically active free cortisol and adrenocorticotropin (ACTH), and the pregnancy-associated blunting of the excursion of plasma cortisol may be explained by an autonomous source of ACTH during gestation.

Multiphasic prolactin secretion during parturition in human subjects

Prolactin (PRL) secretion in the periparturitional period in patients undergoing labor and vaginal delivery follows a remarkable multiphasic pattern not found in patients who underwent elective cesarean section without labor. There is a highly significant decline in PRL levels during active labor which reaches a nadir about two hours prior to delivery. Immediately after delivery, a surge of PRL is noted, reaching peak levels within two hours post partum. Thereafter, PRL levels fall, reaching a second nadir about nine hours post partum, and this low level is maintained for nine to 24 hours after delivery. This multiphasic pattern of PRL secretion is not correlated with changes in serum concentrations of cortisol, progesterone, estradiol, or estrone. PRL levels in all pregnant patients at term were unaffected by the administration of synthetic narcotic analgesic agents, anesthesia, or the stress of operation. It is concluded that PRL secretion in the pregnant patient at term is unresponsive to usual stimuli and that the multiphasic pattern of PRL secretion uniquely found with labor and vaginal delivery may be associated with dopaminergic neuroendocrine processes during human parturition.

Preoperative localization of a testosterone-secreting ovarian tumor by retrograde venous catheterization and selective sampling

Abstract A 20-year-old woman was evaluated to determine the cause of rapidly progressive virilism. Serum testosterone levels were markedly elevated ranging between 6,528 and 13,554 pg. per milliliter and showed no consistent response to either dexamethasone suppression or human chorionic gonadotropin stimulation. Serum androstenedione (1,013 pg. per milliliter) and dehydroepiandrosterone (4.10 ng. per milliliter) levels were normal. Retrograde venous catheterization and selective sampling of the adrenal and ovarian veins showed an enormous step-up of testosterone (293,333 pg. per milliliter) in the right ovarian vein. A hilus cell tumor of the right ovary was found at operation. Following oophorectomy there was a rapid and sustained fall of serum testosterone and a resolution of the patients hirsutism and amenorrhea. This report demonstrates that retrograde catheterization and selective venous sampling can be effectively used preoperatively to localize androgen-secreting tumors.

Effects of exogenous insulin on excursions and diurnal rhythm of plasma glucose in pregnant diabetic patients with and without residual β-cell function

Abstract The relative effects and consequences of split doses of exogenous insulin therapy (two thirds before breakfast and one third before the evening meal) on excursions and diurnal rhythm of circulating glucose during the 24-hour “metabolic clock” were examined. A longitudinal study in pregnant women with maturity-onset diabetes (N = 7) with substantial endogenous insulin secretion and juvenile onset diabetes (N = 6) with no measurable endogenous insulin secretion (judged by C-peptide measurement) was compared with identical studies performed in nondiabetic pregnant control subjects (N = 6). Plasma glucose levels determined at hourly intervals throughout the 24-hour meal-activity-sleep cycles revealed marked excursions of plasma glucose values with exaggerated hyperglycemia during the day hours and relative hypoglycemia at night in both types of diabetic pregnancies as compared to normal control pregnancies. The magnitude of glucose excursion was surprisingly large relative to the degree of increase in the mean 24-hour glucose levels and mean fasting blood glucose values. A striking disparity in the amount of exogenous insulin required to maintain glucose levels and diurnal rhythm toward the normal range in pregnant diabetic patients from second to the third trimester was observed. The degree of exogenous insulin increment imposed by pregnancy (from the second to third trimester) in juvenile-onset diabetes was relatively small (38%) and comparable to the increase in endogenous insulin (32%) found in nondiabetic pregnancies. In marked contrast, among patients with maturity-onset diabetes, in whom substantial endogenous insulin secretion was present, the corresponding increment in exogenous insulin was surprisingly large (98%) without a proportional reduction in 24-hour integrated glucose values. These findings indicate that the effects and consequences of exogenous insulin therapy between maturity-onset diabetes and juvenile-onset diabetes during pregnancy are clearly different. Our data further suggest that peripheral insulin resistance constitutes the major factor accounting for the persistence of hyperglycemia in maturity-onset diabetes. Although the mechanism by which the exaggeration of insulin resistance in maturity-onset diabetes with superimposed pregnancy remains unclear, there are at least three additive contributing events to consider: the inherent defect of insulin resistance in this type of diabetes, the pregnancy-induced insulin resistance, and the reduction in number or affinity of insulin receptors in target tissues occasioned by excessive exogenous insulin treatment.

The impairment of progesterone-induced pituitary release of prolactin and gonadotropin in patients with hypothalamic chronic anovulation

Sequential administrations of progessively increasing amounts of estradiol benzoate (EB) for five days followed by 10 mg. of progesterone (P) elicited a prompt pituitary release of luteinizing hormone, follicle-stimulating hormone, and prolactin in normal women during the early follicular phase but not in women with normogonadotropic hypothalamic chronic anovulation with or without associated hyperprolactinemia. Since hypothalamic dopamine functions as an inhibitor for the secretion of both prolactin and gonadotropin, we postulate that sequential EB-P stimulation for simultaneous release of gonadotropin and prolactin may be mediated by a reduction of hypothalamic dopamine in response to progesterone. The failure of patients with hypothalamic chronic anovulation to respond to this sequential ovarian steroid feedback demonstrated in this study may indicate the presence of dopaminergic dysfunction and that this test may prove to be useful in delineating hypothalamic function in amenorrhea patients.

The N-terminal and C-terminal portions of the atrial natriuretic factor prohormone increase during preeclampsia

The influence of preeclampsia on the circulating concentrations of the 28-amino-acid carboxy terminus (C-terminus) (i.e., atrial natriuretic factor) and the amino terminus (N-terminus) of the 126-amino-acid atrial natriuretic factor prohormone (pro ANF) was studied in the third trimester with the use of three specific radioimmunoassays that recognize: (1) atrial natriuretic factor (i.e., amino acids 99 to 126), (2) the whole 98-amino-acid N-terminus, and (3) amino acids 31 to 67 from the midportion of the N-terminus of the prohormone. The C-terminus was significantly increased (p less than 0.001) in the third trimester in women with preeclampsia, the mean +/- SEM of 15 subjects was 150 +/- 7 pg/ml versus 89 +/- 7 pg/ml in the third trimester in 12 women during normal pregnancies and 65 +/- 2 pg/ml in 19 healthy nonpregnant women. The whole 98-amino-acid N-terminus, likewise, was significantly increased (p less than 0.001) in women with preeclampsia to 4706 +/- 629 pg/ml versus 2160 +/- 79 pg/ml in women in the third trimester of normal pregnancies and versus the circulating concentration of 1847 +/- 127 pg/ml in healthy nonpregnant women. ProANF 31 to 67 mean circulating concentration in preeclampsia was 4638 +/- 725 pg/ml, which was also significantly (p less than 0.001) increased compared with its mean circulating concentration in the third trimester of normal pregnancy of 1758 +/- 83 pg/ml or that in healthy nonpregnant women (1400 +/- 105 pg/ml). The circulating concentrations of both the N-terminus and C-terminus of the atrial natriuretic factor prohormone decreased within 24 hours after delivery in contrast to a normal pregnancy in which they both increase post partum. These results indicate a marked difference in the metabolism of both the N-terminus and the C-terminus of the atrial natriuretic factor prohormone in women with preeclampsia versus that in women with normal pregnancies or that in healthy nonpregnant women.