The effects of human chorionic gonadotropin on growth and steroidogenesis of the human fetal adrenal gland in vitro

This study examined the effects of human chorionic gonadotropin, adrenocorticotropin, human luteinizing hormone, and mouse epidermal growth factor on growth (thymidine incorporation) and steroidogenesis (dehydroepiandrosterone sulfate production) of human fetal zone adrenal cells in monolayer culture. Two preparations of human chorionic gonadotropin extracted from pregnancy urine were used, one highly purified (National Institutes of Health, CR-121) and one less pure (Sigma). Thymidine incorporation was increased twofold to tenfold in cultures exposed to the Sigma human chorionic gonadotropin preparation or to mouse epidermal growth factor as compared to control. Pure National Institutes of Health human chorionic gonadotropin and luteinizing hormone had no effect on growth. When adrenocorticotropin was added alone or in combination with Sigma human chorionic gonadotropin or mouse epidermal growth factor, growth was decreased. Dehydroepiandrosterone sulfate production was stimulated by adrenocorticotropin but not by human luteinizing hormone, human chorionic gonadotropin, or mouse epidermal growth factor. These results suggest that human pregnancy urine contains a growth factor which remains to be identified but that pure human chorionic gonadotropin has no mitogenic or steroidogenic effects on the cultured fetal zone cells of the human fetal adrenal gland.     

Luteotropic effect of human chorionic gonadotropin on human corpus luteum in early gestation (author's transl)

To study the luteotropic effect of human chorionic gonadotropin (hCG) on human corpus luteum in early gestation, serum pregnenolone, 17 alpha OH-pregnenolone, dehydroepiandrosterone, progesterone, 17 alpha OH-progesterone, androstenedione, 20 alpha-dihydroprogesterone and estradiol levels in both ovarian and peripheral venous blood measured by RIA before and after administration of hCG. Seven patients selected for this experiment were 6 to 16 weeks of gestation complicated with fibromyoma. On hysterectomy, 1,000 or 2,000 I.U. of hCG was directly injected into the ovary with corpus luteum to the patients of 6, 12 and 16 weeks of gestation, or 100,000 I.U. of hCG was infused intravenously to the patients of 9 and 14 weeks of gestation. Before 12 weeks of gestation, all free steroid levels except for conjugated steroids in ovarian vein increased promptly 1.8 to 8.9 fold as compared with control levels and stayed high levels for 25 to 60 minutes after administration of hCG. However no marked alteration of these steroids was observed in peripheral vein. In cases studied after 14 weeks of gestation, no marked change of steroid levels in ovarian vein was noticed, while a moderate increase of hCG was observed. These results demonstrated that hCG stimulates the steroidogenesis of corpus luteum in early pregnancy. It was demonstrated that extremely high doses of hCG was required to stimulate steroidogenesis corpus in luteum gravidarum of early gestation.     

Effects of fetal sex, stage of gestation, dibutyryl cyclic adenosine monophosphate, and gonadotropin releasing hormone on secretion of human chorionic gonadotropin by placental explants in vitro

Explants from 16 term and 6 midtrimester placentas were cultured for 6 days. Statistically significant increases in secretion of human chorionic gonadotropin occurred in control medium cultures of both term and midtrimester explants during the 6-day culture period (p less than 0.01). Statistically significant increases in secretion of human chorionic gonadotropin were produced by 2 mmol/L dibutyryl cyclic adenosine monophosphate in both the term (p less than 0.01) and the midtrimester (p less than 0.01) explants. There was no effect of gonadotropin releasing hormone. The ratio of human chorionic gonadotropin secretion from midtrimester explants to that from term explants varied under different conditions, dropping from twentyfold in day 1 cultures to elevenfold for maximum secretion produced after culture in control medium for up to 6 days. A further drop in the ratio to fourfold was observed for the maximal response to 2 mmol/L dibutyryl cyclic adenosine monophosphate treatment. Explants from term female infants produced significantly more human chorionic gonadotropin than those from term male infants (p less than 0.05), but the sex difference disappeared after stimulation with 2 mmol/L dibutyryl cyclic adenosine monophosphate.     

The effect of the dose of human chorionic gonadotropin and the type of gonadotropin stimulation on oocyte recovery rates in an in vitro fertilization program

The effect of the dose of human chorionic gonadotropin (hCG) on oocyte retrieval in an in vitro fertilization (IVF) program was studied. Following ovulation induction using clomiphene citrate and either pure follicle-stimulating hormone (FSH) or human menopausal gonadotropin (hMG), hCG was administered at a dose of 2000 IU (n = 88), 5000 IU (n = 110), and 10,000 IU (n = 104). There was a significantly lower successful oocyte recovery in patients who received 2000 IU of hCG (77.3%) compared with patients who received either 5000 IU of hCG (95.5%) or 10,000 IU of hCG (98.1%; P less than 0.001). There was no significant difference between 5000 or 10,000 IU of hCG. In patients who received 2000 IU of hCG, successful oocyte recovery was significantly lower when pure FSH was used (60%) compared with those who received hMG (84.1%; P less than 0.03). Patients have different thresholds for follicular response to hCG and the recommended minimum dose of hCG should be at least 5000 IU.     

Human chorionic gonadotropin patterns after a single dose of methotrexate for ectopic pregnancy

Objective: The great variability in human chorionic gonadotropin (HCG) levels after a single dose of methotrexate (MTX) for ectopic pregnancy makes it difficult to predict treatment failure. We describe different patterns of HCG levels. Study design: Fifty patients were injected i.m. with 50 mg/m² of MTX for an ectopic pregnancy. Venous blood samples for HCG detection were obtained on the day of treatment (day 0), day 3 and day 7 and weekly until values were undetectable. Patients were classified as: group 1, persistent pathology (n=11); group 2, complete resolution with a decrease of HCG levels at day 3 (n=30); group 3, complete resolution after a rise of HCG values at day 3 (n=9). Statistical analysis was performed using the Mann–Whitney non-parametric test with 95% confidence intervals. Results: Values of day 0 were similar for all the groups. HCG levels of group 3 decreased rapidly after day 3 and at day 7 they were significantly different from levels of group 1. Differences in HCG levels between groups 2 and 3 became indistinguishable from day 21. Conclusion: The observation of patients undergoing resolution after an initial increase of HCG levels justify an expectant management for 1 week in clinically stable patients. The strategy to separate HCG curves in patients undergoing resolution may shed light on the different clinical responses to therapy for ectopic pregnancies. However, the phenomenon of the immediate rise of HCG should be better investigated.     

Relationship of prolactin and estradiol to human chorionic gonadotropin following molar gestation

Serial plasma concentrations of the beta subunit of human chorionic gonadotropin (beta-hCG), prolactin, and estradiol were examined and correlated in 22 women after evacuation of a molar pregnancy for up to 15 weeks into the postmolar phase. The mean levels of prolactin were lower, estradiol levels were higher, and beta-hCG levels were slightly lower but comparable to those reported for women in the first postpartum week. Mean concentrations of all three hormones then declined during the postmolar period; however, beta-hCG remained detectable (greater than or equal to 5 mIU/ml) in some women for up to the fifteenth week, while the nadirs in mean prolactin and mean estradiol levels occurred at 14 and 13 weeks, respectively. The plasma concentrations of beta-hCG correlated with those of prolactin (r = 0.93) and estradiol (r = 0.94), while the levels of the latter two hormones also correlated (r = 0.84).     

The screening of embryonic viability in early asymptomatic pregnancy by a single endosonographic scan associated with plasma human chorionic gonadotropin determination

Purpose Our purpose was to assess, with a prospective study with random assignment of the day of the first evaluation, whether a single transvaginal ultrasonographic evaluation together with the determination of plasma hCG levels could be used to screen embryonic viability in early asymptomatic pregnancy.Methods In 260 pregnant women observed from January 1991 to November 1993 with spontaneous pregnancies where the exact date of ovulation was known, a single transvaginal ultrasonographic measurement of gestational sac with determination of plasma hCG levels, transformed to their natural logarithm (lnhCG), was performed. An abnormal result was defined as a value of lnhCG per mean gestational sac below the 95% lower confidence limit of the viable pregnancy group.Results The sensitivity was 31%, with a specificity of 97%.Conclusion The study demonstrates that this method has a poor predictive capacity to distinguish viable pregnancy from nonviable pregnancy with a kappa value less than 0.4.     

Single‐dose pharmacokinetic study comparing the pharmacokinetics of recombinant human chorionic gonadotropin in healthy Japanese and Caucasian women and recombinant human chorionic gonadotropin and urinary human chorionic gonadotropin in healthy Japanese women

Purpose

Recombinant hCG (r‐hCG) was approved in Japan in 2016. As a prerequisite for a Phase III study in Japan related to this approval, the pharmacokinetic (PK) profile of r‐hCG was investigated.

Methods

An open‐label, partly randomized, single‐center, single‐dose, group‐comparison, Phase I PK‐bridging study was done that compared a single 250 μg dose of r‐hCG with a single 5000 IU dose of urinary hCG (u‐hCG) in healthy Japanese women, as well as comparing a single 250 μg dose of r‐hCG in Japanese and Caucasian women. The Japanese participants were randomized 1:1 to receive either r‐hCG or u‐hCG, while the Caucasian participants were weight‐matched to the Japanese participants who were receiving r‐hCG in a 1:1 fashion. The primary PK parameters were the area under the serum concentration–time curve from time 0 extrapolated to infinity (AUC_0–∞) and the maximum serum concentration (C_max).

Results

The mean serum hCG concentration–time profiles of r‐hCG in the Japanese and Caucasian participants were a similar shape, but the level of overall exposure was ~20% lower in the Japanese participants. For the Japanese participants, r‐hCG resulted in an 11% lower C_max but a 19% higher AUC_0–∞ compared with u‐hCG. No new safety signal was identified.

Conclusion

This study cannot exclude a potential difference in the PK profile of r‐hCG between Japanese and Caucasian participants. However, this study does not indicate that there are clinically relevant differences in the serum PK of r‐hCG and u‐hCG in the Japanese participants.     

The modulating effect of human chorionic gonadotropin on lymphocyte blastogenesis.

Human chorionic gonadotropin (HCG) produced by fetal trophoblastic cells was suggested to play a role in the suppression of maternal lymphocyte response against the fetal allograft. Reports supporting this concept have demonstrated a suppressive effect of crude HCG on lymphocyte blastogenesis. However, similar doses of purified hormone preparations were unable to inhibit lymphocyte stimulation with mitogens. A modulating influence of phenol-free and immunoglobulin-free HCG preparation on lymphocyte blastogenesis is presented. Enhanced lymphocyte stimulation with various mitogens occurred in cultures supplemented with HCG at low doses. On the other hand, higher hormone concentration exerted an inhibitory effect on lymphocyte blastogenesis. An increase in lymphoid cell concentrations was demonostrated in cultures supplemented with the hormone preparation. These observations are compatible with the suggested role of HCG in the maternal tolerance toward a histoincompatible fetus.     

Interrelationships of human chorionic gonadotropin, human placental lactogen, and pregnancy-specific beta 1-glycoprotein throughout normal human gestation

Human chorionic gonadotropin (hCG), human placental lactogen (hPL), and pregnancy-specific beta 1-glycoprotein (PSBG) were measured by radioimmunoassay in 270 samples of serum from women with uncomplicated pregnancies. All three proteins were significantly correlated with each other in individual samples of serum and with the estimated trophoblastic mass during the first trimester. No significant correlation could be demonstrated between the concentrations of hCG and PSBG in maternal serum during the second or third trimesters or between the concentrations of hCG and hPL during the second trimester. Levels of PSBG and hPL in serum were significantly correlated throughout all three trimesters. These findings suggest that the secretion of hCG, hPL, and PSBG may be regulated by similar control mechanisms during the first trimester of pregnancy. However, after this period, the factors that modulate the production of hCG differ from those that regulate the production of hPL and PSBG.     

The effect of severing the spinal cord of fetal lambs on length of gestation

Lambs with spinal cords that had been severed near the head at 50 days of gestation were born after a shortened gestation of about 128 days. Lambs with severed spinal cords born as a twin with an intact lamb had a normal gestation of 148 days. The presence of an intact spinal cord or the signals that it might carry apparently influence the length of gestation in the ewe.     

The effect of luteinizing hormone-releasing factor on human chorionic gonadotropin secretion.

The effect of luteinizing hormone-releasing factor (LRF) on secretion of human chorionic gonadotropin (hCG) by the human placenta in culture was studied. A specific stimulation of hCG secretion was observed. The stimulation of hCG production correlated with the LRF dose in the culture medium. On the other hand, the secretion of human chorionic somatomammotropin was not affected. These data demonstrate a specific action of LRF on placental production of hCG in vitro.     

Crown-rump length and serum human chorionic gonadotropin as predictors of gestational age

The accuracy of fetal crown-rump length measurement and maternal serum human chorionic gonadotropin (hCG) concentration in the prediction of obstetric gestational age was analyzed in a study population of 77 patients for whom time of ovulation was reliably determined. Published nomograms relating maternal serum hCG concentration to gestational age were not found to be valid predictors of gestational age for the study population. Fetal crown-rump length measurement using the uncorrected regression equation of Robinson was found to give the most accurate prediction of gestational age.     

Accuracy of serum beta-human chorionic gonadotropin cutoff values at 42 and 49 days' gestation

OBJECTIVE: The accuracy of serum beta-human chorionic gonadotropin levels as cutoff values for estimating gestational age was studied. MATERIAL AND METHODS: A database was created using information from previously performed research studies, which allowed entry of women both less than and greater than 49 days' gestation, involving medical abortion. Serum beta-human chorionic gonadotropin determinations and vaginal ultrasonography were performed in all studies before treatment. A total of 574 women had data available for analysis. A receiver operating characteristic curve was created to evaluate the predictive value of potential beta-human chorionic gonadotropin cutoff values for 42 and 49 days' gestation. RESULTS: Appropriate serum beta-human chorionic gonadotropin cutoff values for 42 and 49 days' gestation were 23,745 mIU/mL (sensitivity, 96%; specificity, 91%; positive predictive value, 68%; negative predictive value, 99%) and 71,160 mIU/mL (sensitivity, 95%; specificity, 62%; positive predictive value, 76%; negative predictive value, 91%), respectively. Under 42 days' gestation, the serum beta-human chorionic gonadotropin-time relationship appears to be linear, with a greater diversity of individual values after 42 days. CONCLUSION: Serum beta-human chorionic gonadotropin values can be used with reasonable accuracy to screen for a gestational age up to 49 days' gestation.