Congenital adrenal hyperplasia due to 3 beta-ol-hydroxysteroid dehydrogenase (3 beta-ol) deficiency is usually lethal. A partial deficiency in 3 beta-ol has been suggested in some women presenting with androgen excess. In this study, 24 women were investigated who had hirsutism and oligomenorrhea and high serum delta 5 androgens compared to delta 4 androgens. Of these women, 9 had significantly elevated 17-hydroxypregnenolone (17 Preg) to 17-hydroxyprogesterone (17 Prog) ratios when compared to controls under basal conditions. On further testing of 9 women with ACTH, 4 had significantly elevated 17 Preg to 17 Prog ratios. Eight women had elevated ratios of dehydroepiandrosterone sulfate to androstenedione, 4 had elevations of androstenediol (Adiol) to testosterone (T), and 4 had abnormal 17 Preg to cortisol ratios. Only 3 women out of the original 24 selected for study had elevated ratios for all 4 different steroid pairs measured. 17 Prog was normal in these women with 3 beta-ol deficiency in contradistinction to the high levels normally observed in women with congenital adrenal hyperplasia due to 21- or 11-hydroxylase deficiency. It is suggested that the cause of androgen excess in these women is high circulating levels of Adiol and, in part, the slightly elevated unbound T levels in these women. In conclusion, a subtle, incomplete form of 3 beta-ol deficiency may exist in adult women and is manifest by high delta 5 androgens such as dehydroepiandrosterone sulfate and Adiol and normal delta 4 androgens such as androstenedione and T.

A heat- and trypsin-labile follicular fluid protein (FRP) extracted from both human and porcine follicular fluid has been shown to modulate ovarian steroidogenesis. To further investigate the effects of FRP, its effect on the kinetics of 3 beta-hydroxysteroid dehydrogenase activity (3 beta-HSD) was evaluated in cell-free microsomal preparations from human placenta. Test fractions of follicular fluid protein were preincubated with placental microsomes followed by the addition of various substrate concentrations (pregnenolone + NAD). Subsequent progesterone formation was interpreted as the velocity of the reaction. The 50% inhibitory dose (ID50) of FRP for 3 beta-HSD for the three substrate concentrations was 300 micrograms/ml. Although a clear decrease in 3 beta-HSD activity typically occurred after pre-incubation with 730 micrograms/ml of FRP, a paradoxical augmentation in 3 beta-HSD activity was present with the lower concentrations of FRP (10-30 micrograms/ml) and the more concentrated microsomal preparations. Double reciprocal plots of these reactions demonstrated a Km for 3 beta-HSD of 1.8-2.1 X 10(-6) M. Analysis of all reactions was found to be consistent with a noncompetitive mode of enzyme inhibition with an apparent Ki of 120 ng/ml or approximately 10(-8) M assuming a mol. wt of 16,000 Daltons for FRP. This derived Ki for FRP is within the biological concentration of FRP in follicular fluid.

The pronounced hepatic impact of oral ethinyl estradiol has been attributed by some to its so-called first-pass effect through the liver as only some 40% of ingested ethinyl estradiol reaches the systemic circulation. Others believe that ethinyl estradiol exerts its hepatic effects of its chemical composition, specifically its 17α-ethinyl group. In an attempt to resolve this controversy, a study was undertaken to determine whether vaginal administration of ethinyl estradiol can selectively reduce the hepatic effects of oral ethinyl estradiol. To compare the effects of oral and vaginal ethinyl estradiol, a group of postmenopausal subjects received either 5 μg of oral and 20 μg of vaginal ethinyl estradiol or 10 μg of oral and 50 μg of vaginal ethinyl estradiol in either sequence, respectively. Oral ethinyl estradiol was four to five times more potent than vaginal ethinyl estradiol. The potency ratios of the oral-vaginal ethinyl estradiol doses required to suppress follicle-stimulating hormone and luteinizing hormone were 4.4 and 3.2 and those to raise sex hormone-binding globulin binding capacity, corticosteroid-binding globulin binding capacity, and high-density lipoprotein cholesterol as well as lower low-density lipoprotein cholesterol were 3.5, 5.0, 4.2, and 4.2, respectively. These essentially equal oral-vaginal route potency ratios for both central nervous system and hepatic effects indicate that vaginal administration of ethinyl estradiol does not selectively reduce its hepatic impact in relation to its central nervous system effects. The pronounced hepatic effects of ethinyl estradiol are therefore attributed to its chemical composition.

Melatonin levels were determined in plasma samples obtained at 15 minute intervals during a 4-hour period (08:00–12:00 hours) from a normal adult male on 5 consecutive days. On days 1, 2, and 3, the subject was given estradiol valerate (E2) 10μg/kg at the end of each sampling period. An episodic pattern of melatonin secretion was found. Post E2 mean estradiol levels per 4 hours increased and mean melatonin and testosterone levels per 4 hours decreased significantly. A decrease in melatonin levels post E2 is the reverse of the response expected based on nonhuman animal experimental data.

Beta-Endorphin was measured by radioimmunoassay in peripheral plasma of nonpregnant women (58 +/- 2.4 pg/ml, n = 17, mean +/- SE), during the first trimester (47 +/- 2.4 pg/ml, n = 11), the second trimester (33 +/- 1.9, n = 11), and the third trimester (49 +/- 2.7 pg/ml, n = 10) of pregnancy, during early (202 +/- 32 pg/ml, n = 12) and advanced labor (389 +/- 78 pg/ml, n = 10), and 30 to 60 minutes post partum (177 +/- 22 pg/ml, n = 12). Mean plasma levels of beta-endorphin were significantly lower in each trimester of gestation than the levels in nonpregnant control subjects. During labor and the early postpartum period, maternal plasma levels of beta-endorphin were significantly elevated. Furthermore, peripheral plasma levels of beta-endorphin during labor fell from 189 +/- 31 to 97.6 +/- 12 pg/ml (n = 13, p = 0.015) in response to epidural anesthesia, as compared to peripheral plasma concentrations of beta-endorphin of 223 +/- 71 and 193 +/- 47 pg/ml prior to and after injection of saline solution into epidural catheters, respectively, in 10 control subjects. Mean plasma levels of beta-endorphin in patients immediately prior to elective repeat cesarean section who were not in labor (151 +/- 23 pg/ml, n = 15) were significantly higher (p less than 0.005) than the levels in third-trimester control subjects. These data indicate that the pain associated with labor and the psychological stress of anticipating an operation are potent stimuli for the pituitary release of beta-endorphin.

Concentrations of maternal plasma beta-endorphin (beta-EP) as measured by radioimmunoassay decline during pregnancy, reaching a nadir during the second trimester, rise during labor, remain elevated during the early postpartum period and are increased prior to elective cesarean section in the absence of labor. They decline in response to epidural anesthesia during labor and increase during induction of general but not regional anesthesia for cesarean section. Umbilical venous plasma beta-EP levels are not affected by the route or mode of delivery nor the presence or absence of labor, but rise in conjunction with fetal distress. In the presence of fetal distress, umbilical arterial plasma beta-EP levels appear to rise faster than umbilical venous beta-EP concentrations. Amniotic fluid beta-EP levels are higher during the second than third trimester. These data indicate that peripheral plasma beta-EP concentrations reflect stress in both mother and fetus. In the mother, pregnancy itself does not appear to be stressful, whereas pain associated with labor rather than uterine contractions as such increase plasma beta-EP levels. In the fetus, hypoxia and acidosis effectively raise plasma beta-EP concentrations. The origin and physiologic significance of amniotic fluid beta-EP, which appears to be unrelated to fetal maturity, remain to be established.

Plasma β-endorphin was measured in 16 patients in labor prior to and after complete onset of analgesia with 1 mg of morphine administered intrathecally. Human β-endorphin levels were determined by radioimmunoassay following silicic acid extraction of plasma samples and separation of the β-endorphin fraction by gel chromatography. Plasma β-endorphin levels decreased significantly (p < 0.005) after intrathecal morphine from 76 ± 9.7 to 46.3 ± 9.1 fmol/ml (mean ± SE), possibly because of decreased pituitary β-endorphin secretion in response to alleviation of labor pain.

Plasma β-endorphin was measured in 40 healthy pregnant women undergoing cesarean section. Group 1 patients (N = 14) received general anesthesia by rapid-sequence induction and endotracheal intubation with curare, thiopental, and succinylcholine. Anesthesia was maintained with nitrous oxide, oxygen, and muscle relaxant until delivery. Group 2 patients (N = 26) received regional anesthesia (spinal, 14, and epidural, 12). Maternal blood samples were drawn from indwelling venous catheters prior to and after induction of either general or regional anesthesia. Plasma β-endorphin was determined by radioimmunoassay following silicic acid extraction and gel chromatography. In the 14 patients who underwent general anesthesia, the mean (±SEM) plasma β-endorphin increased significantly (p < 0.025) from 46 ± 7.4 to 111.6 ± 8.9 fmol/ml. There was no significant change in plasma β-endorphin level of the 26 patients who underwent regional anesthesia; β-endorphin levels averaged 44.5 ± 5.1 and 47.6 ± 4.8 fmol/ml prior to and after induction of anesthesia, respectively. These data demonstrate that plasma β-endorphin concentrations are elevated following induction of general anesthesia but not with induction of regional anesthesia, which suggests that less stress is associated with regional than with general anesthesia induction in patients undergoing cesarean section.

Twenty-three women with polycystic ovary syndrome, 10 women with hypothalamic-pituitary dysfunction, and 50 control subjects were studied in an attempt to investigate the prevalence of psychological stress and its possible relationship to various hormonal parameters. Norepinephrine (NE) excretion, as reflected by urinary 3-methoxy-4-hydroxyphenylglycol (MHPG), and urinary 3-methoxy-4-hydroxymandelic acid (VMA), platelet serotonin, plasma adrenocorticotrophic hormone (ACTH), urinary free cortisol, serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione (Adione), dehydroepiandrosterone (DHEA), its sulfate (DHEA-S), Δ5-androstenediol (Δ5-Adiol), testosterone (T), and unbound estradiol (E2) were measured. In addition, psychological stress was assessed by means of questionnaires modified from the Schedule of Recent Experiences, in which a Life Events Inventory was scored between 1 and 100. Women with polycystic ovary syndrome had significantly elevated levels of serum LH, LH:FSH ratios, unbound E2, Adione, DHEA, Δ5-Adiol, T, and DHEA-S (p < 0.01). The number of Major Life Events (events scored on the questionnaire above 60) was significantly higher in women with polycystic ovary syndrome than in control women and women with hypothalamic-pituitary dysfunction (p < 0.05). Urinary MHPG and platelet serotonin levels were also significantly higher in women with polycystic ovary syndrome (p < 0.05), whereas VMA was normal. Levels of plasma ACTH and urinary free cortisol were similar in all groups. There was a significant positive correlation between MHPG and DHEA-S, MHPG and LH, and LH and T levels in women with polycystic ovary syndrome and those with hypothalamic-pituitary dysfunction (p < 0.01). VMA also correlated with DHEA-S (p < 0.05). In conclusion, psychological stress may be more prevalent in women with polycystic ovary syndrome and may be associated with elevated levels of MHPG and platelet serotonin. Because we have found that MHPG, but not VMA, correlated with LH, and because both MHPG and VMA correlated with DHEA-S, we hypothesize here that psychological stress and neurotransmitter levels may be linked to some of the hormonal derangements, including inappropriate gonadotropin secretion and elevated adrenal androgen levels in women with polycystic ovary syndrome.

Plasma beta-endorphin (beta-EP) was measured in 48 women. Twenty-three were in labor. In 13 of the 23 patients in labor, beta-EP was determined prior to and after complete onset of epidural anesthesia, and in 10 women, who served as controls, prior to and after injection of saline into the epidural space as part of the loss of resistance technique, but before injection of the local anesthetic. Venous blood also was obtained for plasma beta-EP determinations from 10 healthy non-pregnant women and from 15 patients scheduled for elective repeat cesarean section and who were not in labor. Human beta-EP was determined by radioimmunoassay following silicic acid extraction of plasma samples and separation of the beta-EP fraction by gel chromatography. In the 10 non-pregnant volunteers, plasma beta-EP averaged 11.3 +/- 1.5 fmol/ml (mean +/- SE) as compared with 43.7 +/- 6.5 fmol/ml observed in the 15 women with term pregnancies who were not in labor (P less than 0.005). In the 13 patients in labor who underwent epidural anesthesia, plasma beta-EP concentrations decreased (P less than 0.005) from 54.5 +/- 9.0 to 28.2 +/- 3.5 fmol/ml, whereas there was no significant change in plasma beta-EP levels in the 10 controls who averaged 64 +/- 20.5 and 55.8 +/- 13.6 fmol/ml prior to and following saline injection. These data confirm that plasma beta-EP levels are significantly higher in women with term pregnancies in labor than in non-pregnant women and also demonstrate that epidural anesthesia during labor is accompanied by a significant decrease in maternal plasma beta-EP concentrations.

Twenty-four normal adult female volunteers were dosed orally with a solution and tablet formulation containing the contraceptive combination of norethindrone (NET, 1.0 mg) and ethinylestradiol (EE2, 0.12 mg) in a crossover bioequivalence study. Blood was sampled sequentially following single oral doses and the plasma separated for analysis of NET and EE2 by specific radioimmunoassays. Comparisons of both drugs following a dose in solution and tablets were made with respect to the following parameters: (a) plasma concentrations at each sample time; (b) maximum plasma concentration (Cpmax); (c) time to maximum plasma concentration (Tmax); (d) total area under the plasma concentration vs. time curve (AUC), and (e) plasma half-life (t12). It was found that the tablet and solution doses were bioequivalent with respect to EE2 absorption. However, absorption of NET from solution and tablet doses exhibited significant differences with respect to plasma levels at certain time points as well as AUC (which were higher following the tablet dose), but Cpmax, Tmax and t12 were not significantly different. Pharmacokinetic analysis of both drugs following the tablet dose was carried out using a two-compartment open model. The absorption rate constant (ka) and peripheral to central compartment transfer rate constant (k21) were similar for NET and EE2, but statistically significant differences were observed with respect to the distribution rate constant (α), the central to peripheral transfer rate constant (k12), the overall elimination rate constant (kel), and volume or distribution (V1F). The elimination rate constant (β) for both drugs showed a difference of borderline statistical significance.

Hirsutism can occur in the presence of normal or near normal levels of serum testosterone, unbound testosterone (uT), dehydroepiandrostene sulfate, androstenedione, and dihydrotestosterone. However, we have found that serum androstanediol glucuronide (3 alpha-diol G) is markedly increased in idiopathic hirsutism and it serves as an excellent marker of peripheral androgen metabolism and action. In the present work, we studied 12 hirsute (H) and 12 nonhirsute (NH) patients with polycystic ovary syndrome (PCO) and 13 age and weight matched controls in order to determine if differences in sex steroid levels or peripheral tissue androgen events were associated with hirsutism. Serum unbound estradiol levels and LH-FSH ratios were similar in both groups of women with PCO, and both were significantly higher than levels in controls (P less than 0.05). Whereas serum testosterone, uT, and androstenedione were elevated in both H-PCO and NH-PCO patients compared to controls, the levels in these two groups were similar. Serum dehydroepiandrostene sulfate was higher in PCO patients compared to controls, but H-PCO patients had slightly higher levels than NH-PCO patients. Serum delta 5-androstenediol was also slightly higher in H-PCO compared to NH-PCO patients. Dihydrotestosterone was normal and unconjugated; 3 alpha-diol was higher than normal in both groups of patients with PCO, although H-PCO patients had higher levels than NH-PCO patients. Compared to these relatively minor changes between the PCO patient groups, serum 3 alpha-diol G was markedly elevated in H-PCO patients (approximately 10-fold), yet normal in NH-PCO patients (P less than 0.01). The ratios of serum 3 alpha-diol G-uT were similar in NH-PCO patients and controls, but were elevated in H-PCO patients (P less than 0.01). These data indicate that: 1) women with PCO have increased circulating androgen levels regardless of the presence or absence of hirsutism; and 2) the presence of hirsutism is not only a function of circulating androgen levels, but may also be determined by events in peripheral tissues.

Hirsute and oligomenorrheic women with steroid biosynthetic enzymatic deficiencies (ED) such as 21-hydroxylase (21-HD) deficiency and 3β-hydroxysteroid dehydrogenase-isomerase deficiency (3β-olD) often exhibit inappropriate gonadotropin secretion (IGS) and clinically resemble women with the polycystic ovary syndrome (PCO). Furthermore, the manifestation of androgen excess in ED women varies with the extent as well as the type of enzymatic defect. This study was carried out in order to investigate the causes for the variability in the clinical signs of adrenal androgen excess in ED women and to explain the potential role of adrenal-derived androgens in the development of IGS. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), testosterone (T), androstenediol (A2), dehydroepiandrosterone sulfate (DHEA-S), 17-hydroxyprogesterone (17-OHP), sex hormone–binding globulin binding capacity (SHBG-BC), and unbound T, A2, and E2 were measured in five women with 21-HD, three women with 3β-olD, 22 women with well-documented PCO, and 13 control subjects. In vitro incubation studies were also carried out by adding either T or A2 to sera from four normal women with lowered SHBG-SC in order to study the effect of increasing androgen concentrations on the displacement of T, A2, and E2 from SHBG. Unbound serum E2, A2, and T were elevated in all eight ED women whose SHBG-BCs were lower than those of control subjects (p<0.05). The unbound serum E2 of PCO and ED women showed a positive correlation with LH levels and the LH:FSH ratios (p<0.05) suggesting that unbound E2 which results in part from a lowered SHBG-BC may be responsible for the observed IGS. Four women with 21-HD treated for 1 month with 0.5 mg of dexamethasone nightly had a significant decrease in the percentage of unbound E2 (p<0.05) as well as a normalization of gonadotropins in two of these women. The unbound fractions of T and A2 explain the variable manifestation of androgen excess in ED women. The increased total A2 as well as elevated unbound A2 and T explains the androgen excess of 3 β-olD women who have high levels of weak androgens (RHEA, DHEA-S) and normal total T. In vitro incubation studies indicated that two women with 21-HD had endogenous levels of serum T which could inhibit the binding of A2 and E2, independent of SHBG, resulting in increased unbound fractions of A2 and E2. Similarly five of the eight ED women had endogenous levels of serum A2 which could inhibit steroid binding to SHBG and thereby result in increased fractions of unbound T, A2, and E2. Thus, primarily adrenal-derived androgens, in the case of ED subjects, and increases in the unbound fractions of T, A2, and E2 explain both their androgen excess and in part their IGS. The unbound fractions of T, A2, and E2 are increased because of lowered SHBG-BC, and when T and A2 are sufficiently elevated, because of the inhibition of binding, independent of SHBG levels. It is suggested that this study of women with primarily adrenal androgen excess allows us to speculate on the possible role of the adrenal gland in the androgen excess and IGS of PCO women, many of whom are known to have elevated adrenal androgens. This is discussed and a diagrammatic scheme of our concept of the interrelationship of androgen excess, IGS, and PCO is presented. Hirsute and oligomenorrheic women with steroid biosynthetic enzymatic deficiencies (ED) such as 21-hydroxylase (21-HD) deficiency and 3β-hydroxysteroid dehydrogenase-isomerase deficiency (3β-olD) often exhibit inappropriate gonadotropin secretion (IGS) and clinically resemble women with the polycystic ovary syndrome (PCO). Furthermore, the manifestation of androgen excess in ED women varies with the extent as well as the type of enzymatic defect. This study was carried out in order to investigate the causes for the variability in the clinical signs of adrenal androgen excess in ED women and to explain the potential role of adrenal-derived androgens in the development of IGS. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), testosterone (T), androstenediol (A2), dehydroepiandrosterone sulfate (DHEA-S), 17-hydroxyprogesterone (17-OHP), sex hormone–binding globulin binding capacity (SHBG-BC), and unbound T, A2, and E2 were measured in five women with 21-HD, three women with 3β-olD, 22 women with well-documented PCO, and 13 control subjects. In vitro incubation studies were also carried out by adding either T or A2 to sera from four normal women with lowered SHBG-SC in order to study the effect of increasing androgen concentrations on the displacement of T, A2, and E2 from SHBG. Unbound serum E2, A2, and T were elevated in all eight ED women whose SHBG-BCs were lower than those of control subjects (p<0.05). The unbound serum E2 of PCO and ED women showed a positive correlation with LH levels and the LH:FSH ratios (p<0.05) suggesting that unbound E2 which results in part from a lowered SHBG-BC may be responsible for the observed IGS. Four women with 21-HD treated for 1 month with 0.5 mg of dexamethasone nightly had a significant decrease in the percentage of unbound E2 (p<0.05) as well as a normalization of gonadotropins in two of these women. The unbound fractions of T and A2 explain the variable manifestation of androgen excess in ED women. The increased total A2 as well as elevated unbound A2 and T explains the androgen excess of 3 β-olD women who have high levels of weak androgens (RHEA, DHEA-S) and normal total T. In vitro incubation studies indicated that two women with 21-HD had endogenous levels of serum T which could inhibit the binding of A2 and E2, independent of SHBG, resulting in increased unbound fractions of A2 and E2. Similarly five of the eight ED women had endogenous levels of serum A2 which could inhibit steroid binding to SHBG and thereby result in increased fractions of unbound T, A2, and E2. Thus, primarily adrenal-derived androgens, in the case of ED subjects, and increases in the unbound fractions of T, A2, and E2 explain both their androgen excess and in part their IGS. The unbound fractions of T, A2, and E2 are increased because of lowered SHBG-BC, and when T and A2 are sufficiently elevated, because of the inhibition of binding, independent of SHBG levels. It is suggested that this study of women with primarily adrenal androgen excess allows us to speculate on the possible role of the adrenal gland in the androgen excess and IGS of PCO women, many of whom are known to have elevated adrenal androgens. This is discussed and a diagrammatic scheme of our concept of the interrelationship of androgen excess, IGS, and PCO is presented.

The serum levels of adrenal androgens (aa) are lower in oophorectomized (OO) than in ovulating (OV) women. This study was carried out in an effort to further investigate these findings and to study the effects of administration of estrogen on the levels of aa in OO women. Ten OO and seven OV women participated in this study in which aa were measured basally and after stimulation with adrenocorticotropic hormone (ACTH), both before and 4 weeks after conjugated estrogens (CE). Seven women received 0.625 mg of CE, and five received 2.5 mg of CE. Compared to OV women, OO women had significantly lower levels of androstenedione (Adione), dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), testosterone (T), delta 5-androstenediol (Adiol), and 17 beta-estradiol (E2) (p less than 0.01). In response to ACTH, OO women had smaller responses to Adione (p less than 0.05), DHEA (p less than 0.005), DHEA-S (p less than 0.01), 17-OH progesterone (17 Prog) (p less than 0.01), and 17-OH pregnenolone (17 Preg) (p less than 0.1). Furthermore, after ACTH, the ratio of 17 Prog/Adione was significantly higher in OO women (p less than 0.01), thus suggesting reduced 17,20-demolase (17,20D?) activity. Similarly, OO women had higher ratios of 127 Preg/17 Prog (p less than 0.1), DHEA/Adione (p less than 0.01), and Adiol/T (p less than 0.01), thereby suggesting reduced 3 beta ol dehydrogenase-isomerase (3 beta ol) activity. In response to CE, there was a dose-related increase in aa and cortisol. After 2.5 mg of CE, aa were significantly higher and similar to those levels in OV women. despite the known increases in sex hormone binding globulin-finding capacity and transcortin after estrogen, unbound T increased slightly, as did urinary free cortisol in women treated with 2.5 mg of CE. After treatment with estrogen, there was a dose-related change in the ACTH-stimulated steroid ratios that indicated and increase in 17,20D and 2 beta ol activities. In women who were gien 2.5 mg of CE, these enzyme activities were similar to those in OV women.

The Livingston Reproductive Biology Laboratory, Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Los Angeles, California

17 beta-Estradiol (E2) pellet replacement therapy for oophorectomized women has been shown to be safe and effective. Some investigators have advocated the addition of testosterone (T) pellets for oophorectomized women. This study was carried out to measure the level of androgens in oophorectomized women with and without E2 pellets. The possible modulating role of E2 upon adrenal androgens was investigated as well as the effects of obesity on bound and unbound serum levels of E2 and T. Seven obese patients and eight nonobese normal patients with E2 pellets were compared to nine oophorectomized age- and weight-matched control women not receiving estrogen. Obese patients had higher levels of androstenediol (Adiol) and androstenedione (A) than nonobese patients, yet compared to oophorectomized controls, nonobese patients had higher levels of dehydroepiandrosterone sulfate (DHEA-S) and Adiol. As a group, patients with E2 pellets had higher levels of DHEA-S, Adiol A, and unbound T compared to oophorectomized controls, and their Adiol and total and unbound T levels were similar to those of premenopausal females. Obese patients had lower levels of total E2, yet a higher percentage of unbound E2, resulting in unbound E2 levels which were similar to those of the nonobese women. Unbound T was higher in obese patients compared to the nonobese women and oophorectomized controls. In conclusion, these data suggest that 1) there may be a modulating role of E2 on adrenal androgens exemplified by an increased serum level of delta 5-3 beta-ol androgens in women with E2 pellets, 2) supplemental T implants for oophorectomized women may not be necessary, and 3) obese women with pellets have higher levels of Adiol, A, and unbound T then nonobese women and therefore have a higher ratio of androgen to estrogen.

Antisera suitable for human beta-endorphin and beta-lipotropin radioimmunoassay were developed, and radioimmunoassays were established to measure these peptides in umbilical cord plasma, with silicic acid extraction and gel chromatography used to separate the beta-endorphin from the beta-lipotropin fraction. These two peptides were determined in umbilical venous plasma from 64 newborn infants. Umbilical vein beta-endorphin and beta-lipotropin concentrations averaged 38.5 +/- 3.2 and 50.4 +/- 4.1 (+/- SE) fmoles/ml in the 54 newborn infants without and 115 +/- 18 and 110 +/- 25 fmoles/ml in the 10 newborn infants with apparent fetal distress. Neither the presence or absence of labor nor the route or mode of delivery was found to affect umbilical vein beta-endorphin or beta-lipotropin concentrations. However, cord plasma levels of both peptides were significantly elevated in conjunction with fetal distress, as evidenced by prolonged bradycardia, late and prolonged variable fetal heart rate decelerations, or fetal acidosis. In 18 of 22 pairs of simultaneously measured umbilical venous and arterial beta-endorphin and beta-lipotropin concentrations in newborn infants without apparent intrapartum distress, the venous beta-endorphin concentrations, which averaged 40.4 +/- 3.5 fmoles/ml, were significantly higher than the arterial beta-endorphin levels, with a mean of 28.5 +/- 4.2 fmoles/ml. No significant umbilical arteriovenous concentration difference could be observed for beta-lipotropin. This suggests that at least a portion of the coad plasma beta-endorphin is derived from the placenta. The ratio of umbilical arterial to venous beta-endorphin concentrations rose as the absolute cord plasma beta-endorphin levels increased. Furthermore, both the molar umbilical venous and arterial beta-lipotropin to beta-endorphin ratios decreased significantly in association with intrapartum fetal distress. These data indicate tat the stress-related increase in umbilical plasma beta-endorphin exceeds that of beta-lipotropin and may be, at least in part, of fetal origin. Umbilical venous beta-endorphin and beta-lipotropin levels of neonates whose mothers did not receive meperidine or other narcotics agents did not differ from those of neonates whose mothers were given meperidine or other narcotics during labor. Our data, in conjunction with those of others, are consistent with the hypothesis that fetal hypoxia causes the release of neurotransmitters such as beta-endorphin, which may modulate the regulation of fetal heart rate patterns.