Oral contraceptive absorption and sex hormone binding globulins in obese women: effects of jejunoileal bypass.

Plasma levels of two oral contraceptive gestagens were studied during 24 hour oral challenges in seven morbidly obese women after jejunoileal bypass comparing the results to unoperated normal controls. To study binding and transport of the gestagens, sex hormone binding globulin levels were determined in these patients, in normal-weight controls, and in unoperated morbidly obese patients. The unoperated morbidly obese patients had significantly decreased levels of sex hormone binding globulin, compared to normal-weight controls and to the jejunoileal bypass patients, whose levels were similar to the controls. The jejunoileal bypass patients had a reduced capacity to absorb oral contraceptive gestagens, although the plasma levels were of the same magnitude found in normal subjects using lower doses of gestagens. However, the gestagen to sex hormone binding globulin ratio was lower in jejunoileal bypass patients, implying reduced biologic activity and thus reduced contraceptive efficiency of the gestagen. There were no enzymatic or morphologic signs of liver dysfunction. No correlations were found between plasma gestagen levels and number or volume of stools, fecal fat excretion, or intravenous C-cholic acid load. It is concluded that caution must be exercised in prescribing oral contraceptives to jejunoileal bypass patients.

PIP: 7 morbidly obese women, 20-44 years of age, were followed for 1-3 years after jejunoileal bypass, with particular emphasis on gestagen binding and transport. Plasma concentrations of norethisterone and levonorgestrel were compared in the study group and a control group of nonobese healthy fertile women after ingestion of 3 mg and 0.25 mg, respectively, of these gestagens. Mean plasma levels of norethisterone and levonorgestrel were lower in the obese surgical patients than in controls at 1-8 hours after ingestion; at 24 hours, there was no longer a difference. In contrast, the study subjects had sex hormone binding globulin (SHBG) concentrations that were higher than or of the same magnitude as controls. The norethisterone/SHBG ratio was significantly lower at 1-24 hours after ingestion in jejunoileostomy patients than controls and their levonorgestrel/SHBG ratio was lower at 2, 6, and 8 hours. The lower gestagen concentrations in the study subjects likely indicates that absorption or metabolism has been affected by jejunoileostomy. Thus, the use of low-dose oral contraceptives, especially low-dose gestagen-only mini-pills, is not recommended for women who have undergone jejunoileal bypass given the risk of contraceptive failure.

Progesterone-binding protein in the corpus luteum, blood and lymph of sheep.

A protein which binds progesterone but not cortisol was found in luteal cytosol, utero-ovarian venous plasma, ovarian lymph and jugular venous plasma of sheep. The protein was isolated from other steroid-binding activities present in luteal cytosol and plasma by de-adsorption from hydroxyapatite with 40 mM phosphate. In all cases, it bound progesterone at 4 degrees C with an equilibrium affinity constant of the order of 10(6) l/mol, but did not bind cortisol. After chromatography on hydroxyapatite and Sephadex G-200, the protein obtained from utero-ovarian venous plasma had lost much of its steroid-binding activity, but migrated as a monomer of molecular weight 64 000 in polyacrylamide gel. Bovine luteal cytosol is reported to contain two proteins which bind progesterone similarly. In ruminants, these proteins may participate in the biosynthesis and secretion of progesterone from luteal cells and its transport in blood.

Circulating progesterone, progesterone-binding proteins and oestradiol-17 beta concentrations in the pregnant Cape porcupine, Hystrix africaeaustralis.

Circulating concentrations of progesterone, progesterone-binding plasma proteins (PBPP) and oestradiol-17 beta in pregnant porcupines remained relatively low until Days 25-30 post coitum. Progesterone values peaked (102-180 ng/ml; N = 3) 42-60 days post coitum and the rapid increase in oestradiol-17 beta concentrations approximated that of progesterone with peak values (170-210 pg/ml) being attained 60-85 days post coitum. The pattern of PBPP synthesis, as suggested by circulating concentrations, was closely related to that of plasma progesterone, with values remaining low (less than 20 pmol/ml) until Day 31 post coitum, reaching peak levels at Days 50-56 and Days 73-77 post coitum. The production of PBPP during pregnancy is, as in related New World hystricomorph species, considered to be a mechanism which facilitates a reduction in the rate of progesterone metabolism during pregnancy.

[Changes in index-F and index-delta 4P in normal pregnancy, labor and the puerperium].

Index-F and index-delta 4P (cortisol and progesterone which are not bound to corticosteroid-binding globulin (CBG) in the umbilical cord vein and the maternal blood were determined during pregnancy, at delivery and puerperium. Index-F and index-delta 4P were calculated as the total cortisol or total progesterone X% unbound to CBG divided by 100. The level of index-F showed a gradual rise during pregnancy, and in late pregnancy reached about 1.5 times as high as that of non-pregnant women, whereas the total cortisol level was about 3.3 times. Near delivery, index-F was almost completely stable, but at delivery, it increased suddenly in proportion to the rise in the total cortisol level. This rise is probably due to stress. In the umbilical cord vein blood, the level of index-F was 1.5 times higher than that in the maternal plasma before delivery; however the total cortisol level was lower than that of the maternal plasma. The levels of both index-delta 4P and total progesterone showed a gradual increase during pregnancy in parallel, and each value in late pregnancy was about 4.5 to 4.9 times that of early pregnant women. At or near delivery, the level of index-delta 4P was almost stable and no decrease occurred. In the umbilical cord vein plasma, the levels of index-delta 4P and total progesterone were extremely high. However, the meaning of these results isn't clear.

Effects of intravenous progesterone infusions on the epileptic discharge frequency in women with partial epilepsy.

Earlier work showed that in a group of women suffering from partial epilepsy, there is a decrease in seizure frequency during the luteal phase of the menstrual cycle. Moreover, iv progesterone infusions decrease the discharge frequency from penicillin epileptic foci in cats, when given in doses that reach plasma concentrations as observed during pregnancy. In the present study, iv progesterone infusions, reaching plasma concentrations as during the luteal phase, were given to 7 women with partial epilepsy. The inclusion criterion was that they should have more than one epileptic discharge per 5 min on an ordinary EEG . A 6 h EEG-registration was made. Blank and progesterone solutions were infused for 2 h respectively and the progesterone infusion was followed by a 2 h EEG recording period. 4 of the 7 patients showed a significant decrease in spike frequency during the infusion. In the patients not showing this effect, the plasma progesterone binding capacity was high. The 2 patients with the most marked progesterone effect had low progesterone binding capacity and no antiepileptic treatment. Somnolence during the test might also have influenced the results in 2 of the patients.

Alterations in the androgen metabolism of the female guinea-pig during pregnancy.

The peripheral conversion of testosterone (T) into androstenedione (delta 4) and dihydrotestosterone (DHT) were studied in pregnant (days 32, 48 and 67 post coitum) and non-pregnant anesthetized guinea-pigs by constant intravenous infusion of tritium labeled T. Endogenous levels were measured by radioimmunoassay, and the three labeled androgens (T*, DHT* and delta 4*) counted after celite chromatography. The endogenous T, DHT and delta 4 plasma concentrations were respectively 5, 7 and 20 times higher in pregnant females than they were in cyclic ones. In the non-pregnant guinea-pig, no part of the delta 4 or DHT pools was derived from the peripheral conversion of testosterone. On days 32, 48 and 67 of gestation the fractions of the delta 4 pool originating from T were 9.1, 13.1 and 15.1%, and the fractions of DHT pool coming from T were 5.1, 22.1 and 21.3% respectively.

Progesterone-binding globulin and progesterone in guinea-pigs after ovariectomy, abortion and parturition.

The level of progesterone in the serum of pregnant guinea-pigs which continued their pregnancies after ovariectomy on Day 30 fell and then rose again. In contrast, progesterone-binding globulin (PBG) was apparently not affected. PBG did however fall in guinea-pigs which aborted and also after parturition. It is apparent therefore that high PBG levels were associated with continued pregnancy. The half life of PBG was found to be approximately 2 days.

Progesterone-binding proteins in plasma of guinea-pigs and other hystricomorph rodents.

Progesterone-binding plasma proteins (PBPP, progesterone-binding globulin, PBG, and corticosteroid binding globulin, CBG) have been measured in plasma of guinea-pigs, casiragua, cuis, degu and plains viscacha. During pregnancy PBPP increased to reach peak values between Days 20-25 and Days 50-term in guinea-pigs, immediately before parturition in casiragua, and in mid-gestation in cuis, degu and viscacha. The pattern of PBPP concentration during pregnancy was similar to that of plasma progesterone concentration, and the ratio of molar concentration of PBPP and progesterone was greater than 1 in all species. Plasma proteins were separated by chromatography on SP-Sephadex C-50, and from its chromatographic behaviour and progesterone-binding property evidence was obtained for an anionic, high-affinity PBG in the plasma of all the animals studied during gestation: Electrophoretic mobility of SP-Sephadex-purified PBG applied to 7% polyacrylamide gels differed between species, being highest for casiragua PBG and lowest for guinea-pig PBG. Binding capacities ranged from 0.5 to 4.8 X 10(-6) M, and association constants from 7.6 to 17.4 X 10(8) M-1. Ligand specificities differed between species and marked contrasts were found for certain steroid isomers. The average molecular weights measured by gel electrophoresis of PBG under denaturing conditions were similar in cuis, degu and viscacha and close to PBG I of guinea-pigs, while coypu PBG had a molecular weight of about one half, approximately 75000. It is concluded that PBG has been adopted in pregnancy as a progesterone-conserving mechanism in this suborder of rodents with long gestation periods relative to maternal body weight. Restricted homologies in the physico-chemical characteristics of PBG from various hystricomorph rodents suggest that interspecific differences in structure are considerable.

Concentration and relationship to progesterone of progesterone-binding globulin in pregnant guinea-pigs: measurement by progesterone tracer binding assay.

A single-point progesterone tracer binding assay (TBA) was developed to measure the concentration of progesterone-binding globulin (PBG) in the serum of pregnant guinea-pigs. Tritiated progesterone was added to dilutions of a reference serum, the percentage bound calculated and a standard curve constructed. The amount of progesterone tracer bound to serum samples was determined, and the concentration of binding protein in the sample relative to the reference was calculated. The molar concentration in the reference serum was determined by Scatchard analysis. The TBA could readily process 30 samples per day. There was a rapid rise in PBG concentrations between days 15 and 20 of gestation, in parallel with progesterone concentrations. The molar ratio of PBG: progesterone was approximately 10:1 after this time, until about day 45 when there was an increase in ratio.

Steroid-binding proteins in guinea pig milk and plasma.

The levels of two steroid-binding proteins, progesterone-binding globulin (PBG) (1) and corticosteroid-binding globulin (CBG), present in the plasma of pregnant guinea pigs were determined just before and after parturition. Both PBG (3.37 +/- 2.1 microM) and CBG (10.1 +/- 1.7 microM) were present in high levels just before parturition and were found to decrease with a half-life of 2 days after delivery. PBG and CBG were also found in the milk whey of lactating guinea pigs but at much lower levels (26.5 +/- 12 and 375 +/- 18 nM, respectively, on day 1 post partum). The whey content of each protein declined with a half-life of 3 days. The whey steroid-binding proteins were indistinguishable from their plasma counterparts on the basis of ion exchange and gel filtration chromatographies, sucrose gradient centrifugation, susceptibility to heat denaturation, and hormone binding specificity.

Effects of progestin-estrogen combination and progestational contraceptives on pituitary gonadotropins, gonadal steroids and sex hormone-binding globulin.

The effects of three kinds of hormonal contraceptives on the levels of follicle-stimulating (FSH), luteinizing hormone (LH), estradiol, progesterone, testosterone, and sex hormone-binding globulins (SHBG) in three groups of normally menstruating women were analyzed. During the administration of a very low-dose combination of 150 micrograms of D-norgestrel and 30 micrograms of ethinylestradiol, a progressive suppression of LH, FSH, estradiol, and (to a lesser extent) testosterone levels was observed while progesterone stayed at levels found during the early follicular phase. SHBG levels in these subjects were within the normal range for women. Oral treatment with 0.5 mg of lynestrenol and the intramuscular administration of 200 mg of norethindrone enanthate produced a suppression of LH but not FSH in all cases. Estradiol levels showed peaks in the three women treated with lynestrenol and in half of those treated with norethindrone enanthate, suggesting follicular activity caused by the unsuppressed FSH stimulus; the subsequent elevation of progesterone in two subjects suggested some luteinization, although there was no evidence of an ovulatory surge of gonadotropins. The SHBG in four subjects treated with norethindrone enanthate fell within our normal range for men, and the mean serum testosterone levels fell 40% below the normal basal levels in these cases.