Effect of chorionic gonadotropin, triamcinolone, progesterone and estrogen on enzymes of placenta and liver in rats.

The activity of several enzymes of regulatory importance for the pathways of glycolysis, gluconeogenesis and lipogenesis was investigated in the placenta and liver of pregnant rats and in the liver of non-pregnant female rats. The rats received daily hormonal treatments on Days 15 to 17 of pregnancy and enzyme activities were measured on Day 18. Chorionic gonadotropin induced minor changes in enzyme activity, apart from a decrease in the activity of hepatic enzymes of lipogenesis in non-pregnant rats. Triamcinolone induced a marked increase in enzymes of gluconeogenesis and a decrease in the activity of pyruvate kinase in the liver of pregnant and non-pregnant rats; in contrast, inverse changes in activity, these enzymes were observed in the placenta. This response in the placenta was considered to arise not from direct hormone effect, but from the accompanying hyperglycemia and hyperinsulinemia. Triamcinolone also increased the activity of hepatic acetyl-CoA carboxylase in pregnant and non-pregnant rats, whereas it reduced the activity of this enzyme in the placenta. Estrogen produced changes similar to those of triamcinolone in the liver and placenta, except that it depressed the activity of acetyl-CoA carboxylase in both tissues. Progesterone had little effect on placental and hepatic enzymes. In general, the changes induced by these hormones in the placenta affected fewer enzymes than in the liver, were less extensive in magnitude and not necessarily in the same direction as in the liver. This indicates that the regulatory placental enzymes are subject to specific control mechanisms not necessarily influenced by direct hormone action.

Elevtion of serum testosterone in ovarian hyperstimulation syndrome.

Serum testosterone levels were monitored in female subjects who received therapy with human gonadotropins of urinary origin (menotropins) and human chorionic gonadotropin (hCG). Serum testosterone levels were not elevated in those subjects who did not experience side effects with therapy (Group A); among the other 7 subjects (Group B) with either moderate or severe ovarian hyperstimulation, serum testoterone levels rose distinctly (range 1.4 minus 9.0 ng/ml). Total menotropin dosage and serum estradiol-17beta levels were higher in Group B than in Group A. Ovarian hyperstimulation and elevation of serum testosterone were not restricted to patients with the syndrome of polycystic ovaries.

Changes in activity of enzymes related to glycolysis, gluconeogenesis and lipogenesis in placentae from diabetic women.

The activity of enzymes with a regulatory function in the pathways of glycolysis, gluconeogenesis and NADP-generation was investigated in 50 placentae from normal pregnancies and deliveries, 23 placentae from women with gestational diabetes, and 12 placentae from insulin-dependent patients. In placentae from the gestational diabetic group, the activity of pyruvate kinase and of NADPH-generating enzymes was raised and the activity of enzymes connected to glucogenesis was unchanged. These alterations were attributed to the oversupply of glucose and insulin to morphologically normal and well-oxygenated placental tissue. In the placentae from the insulin-dependent group, the activity of pyruvate kinase was reduced, the activity of NADPH-generating enzymes was enhanced and the activity of those related to the gluconeogenesis was unchanged. It is suggested that this pattern of enzyme changes reflects a reduction in the glycolytic capacity in these placentae, which may be due to inhibition by products of enhanced fatty acid oxidation in diabetes, amino acids and/or by long-term anoxia as a result of uteroplacental circulatory disturbances. The possible relation of reduced energy-forming capacity of the placenta in diabetes to its transport function is discussed.

Lipid deposition and metabolism in rat placenta during gestation.

Changes in placental lipid content in rats at the 15th and 20th days of pregnancy were investigates. It was found that progress of gestation is accompanied by a significant increase in triglycerides per mg placental DNA. Maternal starvation caused additional increase in the placental triglyceride content. By incubation with 14C-oleic acid, it was shown that placenta at term possesses an increased capacity to esterify fatty acids at a wide range of medium oleic acid concentrations. Increase in free fatty acid concentration caused a linear increase of their incorporation into placental lipids. Oxidation of oleic acid into CO2 was also increased with the duration of gestation, but to a lesser degree and over a narrower range of concentration than esterification, suggesting an increased channelling of fatty acids into glycerides.

Recurrent tetraamelia and pulmonary hypoplasia with multiple malformations in sibs.

A term amelic female infant was born to an apparently nonconsanguineous Arab Moslem couple. This was followed by the birth of 4 normal children. Afterwards, in 2 subsequent pregnancies, 2 amelic fetuses were diagnosed by transabdominal ultrasonography in the 18th and 12th week of gestation. Pregnancies were terminated and on autopsy both amelic fetuses had severe lung hypoplasia and aplasia of the peripheral pulmonary vessels. The first fetus also had apparently low-set ears and micrognathia, whereas the last had hydrocephaly and left cleft lip beside the lung hypoplasia and aberrant pulmonary artery. This appears to be a new autosomal recessive malformation syndrome.

Intrapartum bimanual tocolytic-assisted reversal of face presentation: preliminary report.

OBJECTIVE: To design and conduct a mode of vaginal delivery for mentoposterior-presenting fetuses when cesarean delivery is not possible. METHODS: Eleven orthodox Jewish parturients who refused cesarean delivery had intrapartum bimanual conversion of mentoposterior to occipitoanterior presentation, concomitant with ritodrine infusion in ten. RESULTS: Excluding the first case, in which ritodrine was not administered, the maneuver was successful and vaginal delivery was achieved. CONCLUSION: This maneuver, performed with intravenous ritodrine tocolysis, might be an alternative mode of delivery in the presence of mentoposterior presentation when cesarean delivery is not possible. More experience is needed with this technique before it is performed routinely.

Leukocyte alkaline phosphatase relative score and basal body temperature as indicators of ovulation during menstrual cycles terminated by normal full-term pregnancies.

PIP: Leukocyte alkaline phosphatase relative score (LAP-RS) and basal body temperature (BBT) as indicators of ovulation during menstrual cycles terminated by normal full-term pregnancies were assessed in 5 cycles terminated by full-term pregnancies. For 3 of the cycles the LAP-RS appeared on the day of luteinizing hormone (LH) surge and 24 hours after the day of maximal total estrogen excretion. For the remaining 2 cycles the LAP-RS peak occurred the day before the LH surge. A wide range of absolute basal and peak LAP values was observed but the ratio between the basal and peak determination was similar (5.8). This suggested that ovulation may be predicted by a sudden increase of LAP-RS to mean values 5 times higher than the basal preovulatory level. BBTs indicated ovulation more than 24 hours after the LH surge in 2 of 5 cycles, indicating that this test is unsatisfactory for the purpose of predicting and pinpointing ovulation. These data were supported by a 2nd group of 6 women who were monitored by LAP-RS throughout their menstrual cycles, and conceived after insemination and administration of human chorionic gonadotropin.^ieng

Leukocyte alkaline phosphatase monitoring of ovarian function in normal and clomiphene-treated cycles.

PIP: Daily leukocyte alkaline phosphatase activity (LAP), basal body temperature (BBT), fern test (FT) and serum luteinizing hormone (LH) were determined during 15 normal menstrual cycles and 10 cycles treated with clomiphene citrate. A rise in LAP activity, as determined by LAP-relative score (LAP-RS), was observed during the midcycle period. This rise reached peak values on the day of serum LH surge in 60% of cycles. In the remaining cycles, LAP-RS showed peak values 1 day before (8%) or after (32%) LH peak. The mean LAP-RS peak value in clomiphene treated cycles was 13.2, 5-6 times higher than the basic value. The low point of the BBT coincided with the LH SURGE in only 32% of cycles. In 32% the span was more than 1 day before or after LH peak. The day of ovulation as determined by FT corresponded to the LH surge in only 40% of cycles. In 20% of cases, the ovulatory FT reponse occurred more than 1 day before or after LH surge. The results in this study indicated that LAP-RS is a rapid, simple and reliable test for timing of ovulation when carried out daily. It may be valuable in monitoring follicular activity during human chorionic gonadotropin therapy.^ieng

Induction of ovulation with spironolactone (Aldactone) in anovulatory oligomenorrheic and hyperandrogenic women.

Thirteen anovulatory oligomenorrheic, hyperandrogenic, and normoprolactinemic women were treated with spironolactone (aldactone) throughout six consecutive menstrual cycles in a dosage of 100 to 150 mg/day. During this treatment a significant decrease in serum luteinizing hormone (LH), testosterone, prolactin, and 17-ketosteroid values were observed that were accompanied by ovulation in 11 women (85%), according to basal body temperature (BBT) and progesterone values. In addition, improvement of hirsutism was observed in 9 (70%) and restoration of regular cycles in 11 (85%) of the patients. The side effects observed were mild and did not lead to interruption of the treatment. Our data suggest that the antiandrogenic properties of spironolactone render it a suitable agent in the treatment of anovulatory, oligomenorrheic, and hyperandrogenic women.

Induction of ovulation with combined human gonadotropins and dexamethasone in women with polycystic ovarian disease.

A combined treatment of human menopausal gonadotropin (hMG), human chorionic gonadotropin (hCG), and dexamethasone was administered to 27 infertile patients with polycystic ovarian disease who failed to conceive with clomiphene citrate and hMG-hCG alone. Twenty-two (81%) of the patients ovulated according to basal body temperature and progesterone values, and 20 (74%) conceived during one to four treatment cycles. Fifteen (74%) pregnancies terminated in live full-term deliveries (14 singletons and 1 set of twins), and 5 (25%) have terminated in first-trimester abortions. Only one of the treatment cycles was complicated by moderate ovarian hyperstimulation. The average hMG dose required for the induction of ovulation was significantly reduced from 25 ampules with hMG-hCG alone to 18 ampules under the combined treatment (P less than 0.01). The combination of hMG-hCG and dexamethasone is an additional, safe, and effective nonsurgical treatment for women with polycystic ovarian disease who have failed to respond to an hMG-hCG regimen alone.

Low dose ketoconazole attenuates serum androgen levels in patients with polycystic ovary syndrome and inhibits ovarian steroidogenesis in vitro.

OBJECTIVE: To investigate the effects of a low-dose ketoconazole on ovarian steroidogenesis and on serum androgen levels in polycystic ovary syndrome (PCOS). DESIGN: In vitro, human granulosa-luteal cells were incubated with ketoconazole and radiolabeled steroid substrates, to follow their metabolic fate by thin-layer chromatography analysis. In vivo, normally cycling women (n = 7) in their luteal phase were administered one tablet of 200 mg ketoconazole at 8 A.M. Serum steroid levels, sampled basally and at 12 P.M., 4 P.M., and 8 A.M. the next morning, were compared with untreated control group (n = 7) values. Polycystic ovary syndrome women (n = 11) were similarly administered ketoconazole 6 to 10 days after occurrence of spontaneous menses. Adrenal origin of hyperandrogenemia was excluded by stimulation with ACTH and a normal basal DHEAS. The steroid diurnal variation was determined in the same patients a day before treatment. RESULTS: In vitro, ketoconazole selectively inhibited the key steroidogenic cytochromes, namely P450scc, P45017 alpha, and P450arom (IC50 = 0.5 to 1.0 microgram/mL). In vivo, in the luteal phase, ketoconazole transiently decreased serum values (mean +/- SE) of E2 (19.2% +/- 2.1%) and P (38.3% +/- 8.5%) within 4 to 8 hours. The same low-dose ketoconazole, administered to PCOS women, decreased serum values of androstenedione (17.6% +/- 4.7%), T (24.6% +/- 7.6%), and free T (30.7% +/- 7.7%). In contrast, 17 alpha-hydroxyprogesterone increased concomitantly (78.5% +/- 10.8%), suggesting a greater suppressibility of the P45017 alpha lyase activity. The E2 levels in PCOS patients were slightly elevated (29.1% +/- 5.6%), resulting in a 1.7- to 2.3-fold increase of the E2:T ratio. CONCLUSIONS: These findings suggest that a low-dose ketoconazole may facilitate a decreased intraovarian T:E2 ratio, which may prove favorable for follicular maturation in PCOS.

Attenuation of ovarian response by low-dose ketoconazole during superovulation in patients with polycystic ovary syndrome.

OBJECTIVE: To investigate the clinical efficacy of mild inhibition of ovarian steroidogenesis by very low-dose ketoconazole during induction of ovulation in patients with polycystic ovary syndrome (PCOS). DESIGN: Prospective, randomized, cross-controlled study in consecutive cycles. SETTING: Large tertiary care center. PATIENT(S): Eighteen patients with PCOS undergoing hMG superovulation with or without ketoconazole. INTERVENTION(S): A fixed hMG dosage was initiated on cycle days 5-9 in both of the study cycles. Further hMG adjustment was done according to serum E2 levels and follicular measurements. Ketoconazole was administered in one of the cycles by two protocols. MAIN OUTCOME MEASURE(S): Serum E2 and P levels, lead follicles, pregnancy rate, and development of ovarian hyperstimulation syndrome. RESULT(S): Although higher daily hMG doses were needed in cycles with ketoconazole compared with cycles without the drug, the peak E2 levels were substantially lower in the ketoconazole cycles. Although the number of lead follicles did not differ between treatments, the addition of ketoconazole significantly reduced the number of hyperstimulated cycles. Consequently, the cancellation rate dropped dramatically, thus yielding a higher pregnancy rate per patient in the ketoconazole protocols. CONCLUSION(S): Use of a very low dose of ketoconazole during ovulation induction effectively attenuates ovarian steroidogenesis in patients with PCOS. This effect may serve as an adjunct to better control the ovarian response in women who are prone to hyperstimulated cycles.

Elevated serum progesterone levels during pituitary suppression may signify adrenal hyperandrogenism.

OBJECTIVE: To investigate whether elevated serum P levels after pituitary down-regulation signify adrenal enzyme defects or hyperandrogenism. DESIGN: Prospective study. SETTING: Assisted reproduction unit in a university medical center. PATIENT(S): Two hundred twenty-seven IVF patients treated by the long down-regulation protocol. INTERVENTION(S): Oral dexamethasone (DEX) administration if P level exceeded 0.8 ng/mL (conversion factor to SI unit, 3.180) after pituitary suppression. MAIN OUTCOME MEASURE(S): Serum concentrations of P, E2, LH, DHEAS, and 17 alpha-hydroxyprogesterone and ACTH stimulation tests. RESULT(S): In eight patients (3.5%), serum P levels exceeded 0.8 ng/mL and E2 and LH levels confirmed pituitary down-regulation. Mean DHEAS levels in the patients in this group were significantly higher than in the other patients. All eight patients demonstrated a significant decrease in serum P level after DEX administration. In five patients the ACTH stimulation test suggested an adrenal defect. Five pregnancies were achieved after the addition of DEX to the treatment protocol. CONCLUSION(S): High serum P levels after pituitary down-regulation appear to be of adrenal origin and may be the first indication of an adrenal enzyme defect. Further investigation such as an ACTH stimulation test is recommended, followed by treatment with DEX if indicated.

Chloroquine treatment of interstitial lung disease in children.

Seven children aged 3 months to 11 years with histologically confirmed interstitial lung disease (ILD) [6 with desquamative interstitial pneumonitis (DIP) and 1 with chronic interstitial pneumonitis] were treated with chloroquine, 10 mg/kg/day. One patient, diagnosed late in the course of the disease, died after three weeks of treatment, despite the addition of systemic corticosteroids. Another patient responded to combined therapy with chloroquine and prednisone and had a normal lung biopsy after 6 months of treatment. He underwent surgical repair of mitral valve stenosis and died after extensive brain infarction. The other 5 patients responded well to chloroquine therapy with major improvement in oxygenation within a few weeks and in lung function over the next few months. They remained well clinically and physiologically, including a normal response to incremental exercise, during a mean follow-up period of 9.8 years (range 3.5 to 15.7 years). None of the patients has developed retinopathy or any other ocular complication. Bronchoalveolar lavage was a useful tool for evaluation of the activity of the disease (predominance of neutrophils) in 3 out of 4 patients. We suggest that chloroquine should be considered as an effective treatment in ILD in children. Incremental exercise test may be helpful for routine follow-up and evaluation of the efficacy of a specific treatment.

Cocaine: maternal use during pregnancy and its effect on the mother, the fetus, and the infant.

Cocaine was previously regarded as a soft drug causing only mild damage. Its use during pregnancy, however, creates a variety of grave medical problems which necessitate immediate attention not only on the part of internists and psychiatrists but also, and more particularly, by obstetricians and pediatricians. The pregnancy of a cocaine-using woman must be carefully managed and regarded as a high-risk one. This in view of the numerous obstetric risks caused by the drug, notably premature separation of the placenta, increased incidence of stillbirths, congenital malformations, premature births, and intrauterine growth retardation. The neonatal monitoring must be focused on prevention of complications resulting from the withdrawal syndrome and associated conditions such as pneumonia, severe weight loss, and contagion from the mother. Moreover, efforts must be made to ensure a strict observation of the infant outside the hospital in view of the far greater incidence of idiopathic infant death in such cases. Owing to the sharp rise of the regular and occasional use of the drug and since pregnant women tend on anamnesis to deny any drug taking, we recommend a test of maternal urine for cocaine and other drugs whenever a suspicion to this effect arises. It is also advisable to test for the presence of such drugs in the urine of the neonate in cases of reasonable suspicion of maternal use during pregnancy, though a negative outcome of the urine test naturally does not rule out a possible use. Strict monitoring of positive cases, accompanied by preventive treatment, may contribute a great deal toward a reduction of perinatal morbidity and mortality associated with cocaine use use.

Bell palsy complicating pregnancy: a review.

UNLABELLED: The aim of the present work was to review the published evidence on the association of Bell palsy (BP), an acute idiopathic peripheral facial paralysis of unknown etiology, with pregnancy. Reports have shown that women of reproductive age are affected two to four times more often than men of the same age, and pregnant women 3.3 times more often than nonpregnant women. The apparent predisposition of pregnant women to Bell palsy has been attributed to the high extracellular fluid content, viral inflammation, and immunosuppression characteristic of pregnancy, but findings are controversial. Most cases of Bell palsy occur in the third trimester or the puerperium. Onset is acute and painful. Some authors suggest that Bell palsy increases the risk of hypertension and toxemia of pregnancy, whereas the pregnant state, in turn, may affect the course and severity of disease. Recovery is usually good; poor prognostic markers are recurrence in subsequent pregnancy and bilateral disease, both of which are rare. Neonatal outcome is apparently unaffected, although this has been studied rarely. The preferred mode of management remains undecided; it is usually confined to supportive care. Corticosteroids in pregnancy are controversial. We think clinicians should be aware of these findings to avoid unnecessary testing and treatment and to help the patient cope with this acute, painful disease. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader will be able to identify the potential etiologies of Bell palsy associated with pregnancy and to describe the clinical presentation of this condition in pregnancy and its likelihood for recovery.

Induction of ovulation by combined clomiphene citrate and dexamethasone treatment in clomiphene citrate nonresponders.

Fifteen anovulatory, oligomenorrheic, hyperandrogenic and normoprolactinemic women who failed to respond to prolonged clomiphene citrate (CC) treatment, were subsequently treated with CC and small doses of dexamethasone (Dex). Twelve (80%) of the patients ovulated according to BBT and progesterone values, and 7 (49%) conceived during 3--6 treatment cycles. Five of these pregnancies terminated in live, single, full term deliveries, one set of twins and one first trimester abortion. It is concluded that a regimen of combined CC and a small dose of Dex may be offered to CC nonresponders as an effective alternative to Menotropins--HCG treatment.

Ovulation induction with pulsatile human menopausal gonadotropin (HMG) administration.

A computerized pump for continuous pulsatile HMG administration was used with 5 patients having prolonged anovulatory infertility, for 14 consecutive cycles. All of these women had previously failed to respond to various treatment regimens, or repeatedly developed ovarian overstimulation syndrome. In 12 out of 14 cycles, ovulation was detected by hormonal and ultrasonic evaluation, and pregnancy was achieved in 2 out of 5 cases. A mild form of overstimulation was observed in only 3 out of 14 cycles. A summary of the results of the present and similar previously published series demonstrated overall ovulation and pregnancy rates of 75% and 23.5% respectively. We concluded that inducing ovulation by administering pulsatile HMG is an appropriate alternative method of treatment when ovulation and conception fail with conventional regimens.

High incidence of preeclamptic toxemia in patients with polycystic ovarian disease.

The incidence of preeclamptic toxemia (PET) was investigated in 72 anovulatory, oligomenorrheic and previously nulliparous women who conceived after an induction of ovulation. One-thousand consecutive spontaneous pregnancies and 1,000 pregnancies of primiparae were used as control groups. The anovulatory group consisted of 33 consecutive well-documented cases of polycystic ovarian disease (PCO) and 39 anovulatory patients in whom PCO was excluded (A-NPCO). The results indicate that pregnancies after induction of ovulation are accompanied with a higher incidence of PET. The rate of this disorder was significantly higher in PCO groups than in A-NPCO women (28.5 vs. 4%), when calculated per number of all pregnancies. The difference between the incidence of PET in PCO, A-NPCO, control primiparae and normal control patients was even more pronounced when calculated on the basis of the number of patients (54.5, 12.5, 11 and 2.5%, respectively). Overproduction of steroid hormones, especially androgens, was suggested as the main factor for the appearance of PET in PCO patients.

Effect of ketoconazole on steroidogenic human granulosa-luteal cells in culture.

Ketoconazole (KCZ), a widely used antifungal drug, has been reported in humans to inhibit adrenal and testicular steroidogenesis by interfering with the cytochrome P-450-dependent enzymes. The purpose of this study was to investigate the drug effect on steroidogenic human granulosa-luteal cells, obtained by follicular aspiration from mature follicles of gonadotropin-treated women. Cells were cultured in long-term monolayers, and the steroid production was assayed by radioimmunoassay. A profound inhibition of ovarian cell secretion of progesterone (P), testosterone (T) and estradiol was found. At a low concentration (5 micrograms/ml), KCZ failed to inhibit the conversion of pregnenolone to P, mediated by the non-cytochrome 3 beta-hydroxysteroid dehydrogenase-isomerase enzyme (3 beta-HSDH). At a similar concentration, P secretion by human chorionic gonadotropin (hCG; 100 mIU/ml) -treated cells was decreased by 68% (P less than 0.001) and therefore, an inhibitory effect of KCZ on the cholesterol side-chain cleavage enzyme (P-450SCC) was assumed. A similar marked inhibitory effect (81%) (P less than 0.001) on T secretion was observed for hCG-stimulated cells given pregnenolone as substrate. The P-450 aromatase was profoundly inhibited (86%) (P less than 0.001) in a reversible manner, by a similar concentration (5 micrograms/ml) of KCZ. These findings suggest that KCZ has the capability to suppress human ovarian steroidogenesis similarly as in testis and adrenal.