Correlations between periovulatory serum and follicular fluid CA-125 and granulosa cell hormones after controlled ovarian hyperstimulation.

OBJECTIVE: To determine the presence and concentration of CA-125 in periovulatory follicular fluid (FF) and serum after controlled ovarian hyperstimulation and to determine if the CA-125 in these two compartments could be related to granulosa cell markers such as inhibin or estradiol. STUDY DESIGN: Fifteen women undergoing controlled ovarian hyperstimulation for in-vitro fertilization-embryo transfer were studied. A transvaginal, ultrasound-guided follicular aspiration was performed. CA-125, inhibin, estradiol and FSH were measured in FF and serum. Pearson and Spearman's Rank Correlation tests were performed. RESULTS: CA-125 was measurable in 59% of follicles. Values ranged from undetectable to 3630 U/ml. Serum CA-125 ranged from undetectable to 126 U/ml. CA-125 and inhibin correlated negatively in FF and positively in serum. CONCLUSION: CA-125 was present in significant but variable concentrations in 59% of periovulatory follicles. A negative correlation was noted between CA-125 and inhibin or estradiol in the FF and a positive correlation with serum inhibin. No correlations were noted to oocyte retrieval or fertilization.

Sensory thresholds during the antepartum, intrapartum and postpartum periods.

The present exploratory study measured pain and tactile thresholds in response to mechanical stimulation of the hand before labor, during labor, and after parturition in women. In women who had Lamaze childbirth preparation (but not in women who did not have childbirth preparation), pain thresholds were significantly higher during labor (determined up to 8 cm cervical dilatation) than prior to labor and 24 hours postpartum. Tactile thresholds did not change during any of these conditions. These findings support earlier findings in this laboratory that vaginocervical mechanostimulation elevated pain thresholds in human and animal subjects, and more recent findings that pain thresholds increased in rats during delivery of individual young. The present findings suggest that an endogenous process that attenuates the pain of parturition is activated when the cervix dilates during labor.

Water and salt conservation in the human fetus and newborn. I. Evidence for a role of fetal prolactin.

A study was performed on 94 women delivering at 34-44 weeks gestation, whose pregnancies were uncomplicated to determine the role of PRL in human fetal and neonatal salt and water conservation. Ultrasonic estimation of amniotic fluid (AF) volume and sampling of maternal blood, AF, cord blood, and 2-h neonatal blood were performed to analyze PRL, osmolality, sodium ion concentration ([Na]), and blood solids [hematocrit (Hct), total serum solids (tss), and total protein concentration]. In this report, which addresses the role of fetal PRL, Pearson correlations showed the following significant relationships: 1) approximation of cord serum osmolality and [Na] in cord and maternal serum, as well as parallel changes in cord blood Hct, tss, and total protein; 2) reduced estimated AF volume and increased AF osmolality in the face of elevated cord serum osmolality and [Na]; 3) a shift toward normal in cord Hct and tss over the first 2 h of neonatal life after an initially increased or decreased cord serum osmolality, [Na], Hct, or tss; and 4) relationship between fetal pituitary PRL levels of 230 micrograms/L or less and cord serum osmolality, [Na], and Hct. The entire range of cord serum PRL levels correlated with changes in AF osmolality and [Na] as well as with neonatal changes in Hct and tss. These findings support the hypotheses that osmotic equilibrium exists between maternal and fetal circulations; that disturbances in this balance lead to changes in fetal and neonatal water excretion; and that fetal PRL, stimulated by increases in cord serum osmolality and [Na], acts as an antidiuretic, leading to restoration of the offspring's extracellular fluid volume.

Expectant management of presumed ectopic pregnancies.

Thirteen patients with presumed diagnosis of unruptured ectopic pregnancy underwent expectant management. The diagnosis was based on the criteria of clinical stability, no intrauterine gestation sac by sonogram, and falling beta subunit human chorionic gonadotropin titer. The diagnosis also was based on no gross evidence of trophoblastic tissue on sharp curettage and alteration in uterotubal anatomy at laparoscopy. In these 13 patients, titers continued to drop and were below assay detectability (1.5 miu/ml) by 1 to 5 weeks. Only one patient required a laparotomy. Hysterosalpingograms in ten of the patients showed normal, patent tubes in seven. One patient had cornual occlusion and two showed a hydrosalpinx with spillage. A second laparoscopy in seven patients demonstrated normal tubes in all but one. At present, three patients have delivered term infants and two have had first trimester spontaneous abortions. These observations suggest that expectant management of tubal pregnancies is appropriate under rigidly controlled conditions.

Heterogeneous distribution of serum prolactin values in apparently healthy young women, and the effects of oral contraceptive medication.

Controversy over effects of oral contraceptives (OCs) on serum prolactin (PRL) levels from retrospective studies suggested performing a prospective study. Statistical analyses of PRL levels in 552 reproductive-age, nonmedicated women indicated a provisionally lognormal distribution of values less than 15 ng/ml, contaminated by a small number of abnormally high values less than or equal to 90 mg/ml. Truncated samples were used to estimate a "normal range" of PRL levels for three subsets of the study sample, classified according to number of weeks after pregnancy. Fifty-microgram estrogen-containing OCs doubled basal PRL levels at 5 to 8 weeks in those whose initial control values fell below 15 ng/ml, but the PRL elevation was no longer evident at 6 months of drug use. These OCs induced a small but significant lowering of PRL at 5 to 8 weeks in those with control levels of 15 ng/ml or higher. Thirty-five-microgram estrogen-containing OCs failed to alter PRL levels at 5 to 8 weeks in those with control values less than 15 ng/ml.

The role of lactogenic hormones in the pregnant woman and the fetus.

Evaluation of the roles of prolactin and placental lactogen in pregnancy in primates has revealed mammotropic, fetal osmoregulatory, metabolic, and steroidogenic roles, which appear to protect the uterine contents during late pregnancy and prepare the fetus for the changes in nutrition at the time of delivery.

Evaluation of postterm pregnancies with maternal serum placental lactogen and alpha-fetoprotein concentrations.

Studies of maternal serum placental lactogen (hPL) levels in 70 women delivering beyond 42 weeks of gestation revealed significantly lower levels of hPL when the offspring had one or more of ten signs of postmaturity or distress. A sequential combination of hPL measurements and intrapartum fetal heart rate monitoring (FHRM) (performed in 61 patients) gave a high degree of prognosis (75% of abnormalities detected, 88% with normal tests having no abnormalities). Considered separately, neither maternal serum hPL levels nor FHRM predicted abnormalities in the offspring to the same high degree. On the other hand, hPL could not be correlated with staining, desquamation, and the presence of meconium in the amniotic fluid at delivery, these criteria being considered separately or in combination. Maternal serum alpha-fetoprotein (AFP) levels during late gestation showed considerable variation and did not permit distinction between pregnancies with or without an abnormality in the offspring.

New technique of injection of estradiol into preoptic-anterior hypothalamic area of newborn rats: technique limiting diffusion and duration, with preliminary results on postpuberal block of ovulation.

Previous studies have shown that sc administration of androgen or estrogen into newborn female rats will disturb postpuberal ovulatory function, as evidenced by a higher incidence of vaginal estrus, few ovarian corpora lutea, and the abolition of estrogen-induced luteinizing hormone surges after ovariectomy and chronic estrogen maintenance. Studies of the uptake of labeled estrogen and intracerebral lesion studies have indicated the preoptic area and anterior hypothalamic nuclei (POA-AH) as possible sites of steroid uptake and control of certain sexual functions in the rat. Attempts to localize the site of steroid effects to the POA-AH of newborn rats by chronic implants have been hampered by lack of definition of extent of localization in space and time. The present study introduces a microinjection technique for the delivery of subpicogram quantities of estradiol to these areas of the central nervous system in newborn rats, and statistically defines the extent of steroid localization in three dimensions as well as the duration of exposure. Delivery of estradiol by this method in the POA-AH region yielded an increased incidence of postpuberal vaginal estrus; a decrease in the number of corpora lutea; and in many but not all, led to abolition of estrogen-progesterone induced LH surges after castration and estrogen replacement. Injection 0.5 mm more caudad did not result in blockade of the estrous cycle.

Binding of prolactin by fetal rhesus cell membrane fractions.

Interest in possible physiologic roles of prolactin in the developing fetus led to the present study of affinity of human prolactin to fetal rhesus cell membrane fractions. The fractions were prepared by ultracentrifugation and their composition confirmed by electron microscopy. The cell membrane preparations were derived from the fetal placenta, liver, lung, myocardium and brain. Kinetic studies showed apparent binding affinity constants for 125I-labeled human prolactin (hPRL) of the order of 10(9)M-1 and capacities of from 3 ng to over a microgram per organ in late pregnancy for all of these tissues except brain. The calculated binding capacities, although probably underestimated, were found sufficiently high to insure that a portion of maternal and fetal prolactin exists in bound form to fetal tissues, consistent with possible roles in the regulation of fetal tissue cellular function, and provided they have access to circulating PRL.

Amniotic prolactin control over amniotic and fetal extracellular fluid water and electrolytes in the rhesus monkey.

Administration of 1-10 mg ovine pituitary prolactin (oPRL) into the amniotic fluid of 10 rhesus monkeys in the last third of gestation consistently caused a decrease in amniotic fluid volume not seen when saline, vasopressin, or bovine serum albumin were injected into 9 other monkeys. The effects lasted for 24 h. Intraamniotic injection of 10 mg oPRL prevented or reversed a doubling of water and electrolyte content of the fetal extracellular fluid (ECF) volume in the face of hypertonic amniotic fluid. Efflux of these substances from the fetal ECF in the face of hypotonic amniotic fluid was similarly prevented or reversed by intraamniotic prolactin injection. Ovine PRL had no effect on fetal ECF water and electrolytes in the face of isotonic amniotic fluid. Possible sites of these oPRL effects were amnion, placenta, fetal lung and/or fetal gastrointestinal tract.

Pituitary gonadotropin response in women with idiopathic hyperprolactinemia.

Inappropriate lactation and idiopathic hyperprolactinemia are frequently associated with amenorrhea. In these individuals, peripheral levels of follicle-stimulating hormone (hFSH) are usually normal, and luteinizing hormone (hLH) levels are often found in the low-normal range. The present study was undertaken to evaluate the functional capacity of the pituitary by the response of hFSH and hLH to synthetic gonadotropin-releasing hormone (Gn-RH). Six women with amenorrhea, inappropriate breast secretion, and idiopathic hyperprolactinemia (prolactin levels ranged from 45 to 355 ng/ml) were given 100 mug of Gn-RH intramuscularly. Serum hFSH and hLH levels were assessed in samples obtained at 15-minute intervals over the next 2-hour period. Initial hFSH levels were normal in all women, with a mean of 242 +/- 72 ng/ml. The absolute increase after Gn-RH administration averaged 486 +/- 193 ng/ml. Serum hLH was below normal in three of the six women, and normal in the remaining three women initially. The absolute increase averaged 1308 +/- 315 ng/ml. The greatest percentage increase in hLH was found in the women with the subnormal basal titers. In these women, hLH rose from a mean of 22 ng/ml to a mean of 1092 ng/ml. These data demonstate an exaggerated increase in hFSH and hLH levels after exogenous Gn-RH administration. This suggests that the amenorrhea associated with elevated serum prolactin levels is principally of hypothalamic origin.

Ovarian response to exogenous gonadotropins in women with elevated serum prolactin.

To determine if elevated serum prolactin hPRL inhibits ovarian steroidogenesis and contributes to the amenorrhea associated with galactorrhea syndromes, the following study was performed. Four women with amenorrhea, galactorrhea, and elevated serum hPRL levels were treated with menopausal gonadotropins (Pergonal) for the associated infertility. Urinary estrogen response was comparable to that in normal ovulatory women in each patient. Ovulation occurred in 3 of the 4 women with resultant conception and normal pregnancies. There was no evidence to support the contention that elevated hPRL interferes with ovarian function.

Response of serum prolactin to exogenous stimulation.

Previous observations by other workers indicating suppression of serum prolactin (hPRL) by water loading could not be confirmed. Sequential testing using an acute water load in patients with various clinical diagnoses did not aid conclusively in differentiating functional hyperlactinemic states from pituitary adenoma. It was of interest that the acute ingestion of water resulted in a triphasic response in serum hPRL levels. The response to breast stimulation was more marked in patients with excessive breast hypertrophy and galactorrhea. This was in contrast to patients with hypo- or hyperthyroidism, anorexia nervosa, and our normal subjects. In response to breast stimulation, there was no difference among the normal group, women with functional hyperlactinemia, and patients with proven pituitary adenoma. When they were compared with other patient groups in this study, marked responsiveness was found in patients with amenorrhea and galactorrhea, amenorrhea with elevated hPRL levels without galactorrhea, breast hypertrophy, and adrenal overactivity in response to these two stimuli. The physiologic mechanisms resulting in the increase in serum hPRL levels seen in these patients remain unclear at the present time.

Amenorrhea and galactorrhea: results of therapy with 2-Brom-alpha-ergocryptine (CB-154).

Administration of Brom-ergocryptine (CB-154) has a dramatic effect on breast secretion. Inhibition of lactation occurs within three to four weeks in women with amenorrhea and galactorrhea. Resumption of normal ovulatory function was documented by serum progesterone levels, as well as pregnancy, in three of four women attempting to conceive. Serum prolactin levels become normal following initiation of Brom-ergocryptine. Discontinuation of Brom-ergocryptine was found to result in a return of both inappropriate lactation and elevation of serum prolactin in this study. No deleterious side effects of Brom-ergocryptine have been found in any of the volunteers either clinically or on the basis of sequential laboratory studies.

Prostaglandin content of human endometrium.

Prostaglandin levels in 46 human endometrium specimens were determined and expressed as both total uterine content and on a dry weight basis. Concentrations of PGF2alpha and PGE did not differ significantly between specimens obtained during the proliferative or secretory phases of the menstrual cycle. There was, however, a fourfold higher total uterine content of prostaglandins during the secretory phase. There was also a more than fourfold higher level of PGF2alpha than of PGE during the secretory phase. The two types of prostaglandins were present in nearly equal amounts during the proliferative phase. Atrophic endometrium was characterized by a high concentration of prostaglandins, but a low total amount consisting of nearly equal amounts of PGF2alpha and PGE.

PIP: The study objective was to establish the endogenous levels of prostaglandins in endometrium by specific radioimmunoassays and to express the determined values in terms of dry weight of tissue examined. Endometrial specimens were obtained from 46 patients (age range 23-59 years) at Magee-Womens Hospital in Pittsburgh who were undergoing medically warranted abdominal or vaginal hysterectomy. Each uterus was bisected vertically within 5 minutes of the final clamping of the uterine blood supply. The endometrium was sharply dissected from the more normal-appearing half uterus and homogenized at high speed for 5 minutes in methanol. The remaining half of the uterus was examined histologically and categorized as being obtained during either the proliferative or the secretory phase of the menstrual cycle or as atrophic. Radioimmunoassays were performed with regents obtained from Clinical Assays, Inc. (Cambridge). All 46 specimens were analyzed for prostaglandin F2alpha (PGF2alpha). 3 were excluded because their antigenic behavior did not parallel that of known PGF2alpha. Of 28 specimens analyzed for prostaglandin E (PGE), 2 were excluded because of nonparallelism. Concentrations of PGF2alpha and PGE did not differ significantly between specimens obtained during the proliferative or secretory phases of the menstrual cycle. There was a 4-fold higher total uterine content of prostaglandins during the secretory phase, and there was a more than 4-fold higher level of PGF2alpha than of PGE during the secretory phase. The 2 types of prostaglandins were present in nearly equal amounts during the proliferative phase. Atrophic endometrium was characterized by a high concentration of prostaglandins but a low total amount consisting of nearly equal amounts of PGF2alpha and PGE.