Immediate pre-ovulatory administration of 30 mg ulipristal acetate significantly delays follicular rupture.

BACKGROUND: Current methods of hormonal emergency contraception (EC) are ineffective in preventing follicular rupture when administered in the advanced pre-ovulatory phase. This study was designed to determine the capacity of ulipristal acetate (UPA), a selective progesterone receptor modulator developed for EC, to block follicular rupture when administered with a follicle of >or=18 mm. METHODS: This was a double-blind, crossover, randomized, placebo-controlled study. Thirty-five women contributed with UPA (30 mg. oral) and a placebo cycle. Serial blood sampling for luteinizing hormone (LH), estradiol and progesterone measurements and follicular monitoring by ultrasound were performed before and for 5 days following treatment. Follicular rupture inhibition was assessed in the overall study population and in subgroups of women stratified by when treatment was administered in relation to LH levels (before the onset of the LH surge, after the onset of the surge but before the LH peak or after the LH peak). RESULTS: Follicular rupture failed to occur for at least 5 days following UPA administration in 20/34 cycles [59%; 95% confidence interval (CI) (40.7-75.4%)], whereas rupture took place in all cycles within 5 days of placebo intake. When UPA was administered before the onset of the LH surge, or after the onset but before the LH peak, follicle rupture had not occurred within 5 days in 8/8 (100%) and 11/14 [78.6%; 95% CI (49.2-95.3)] cycles, respectively. In contrast, when UPA was given after the LH peak, follicle rupture inhibition was only observed in 1/12 [8.3%; 95% CI (0.2-38.5)] cycles. CONCLUSIONS: This study demonstrates that UPA can significantly delay follicular rupture when given immediately before ovulation. This new generation EC compound could possibly prevent pregnancy when administered in the advanced follicular phase, even if LH levels have already begun to rise, a time when levonorgestrel EC is no longer effective in inhibiting ovulation.

Endometrial effect of progesterone delivered by vaginal rings in estrogen-treated postmenopausal women.

AIM: The type of estrogen and progestin as well as their doses, route and regimens of administration may each affect the benefit-risk profile of postmenopausal hormone therapy. The aim of this study was to evaluate the endometrial effect of progesterone released continuously from a vaginal ring, combined with transdermal estradiol in postmenopausal women. METHOD: Forty-four postmenopausal women participated in a randomized, double-blind, dose-finding study evaluating two hormonal treatments, combining 50 microg/day of estradiol delivered by transdermal patches and either 0.5-g or 1-g progesterone vaginal rings (PVR) given for 12 weeks. The effect on the endometrium was assessed by histology and the detection of the proliferative marker Ki-67. We also measured the serum concentration of estradiol and progesterone, the tissue concentration of progesterone and the immunolocalization of estradiol and progesterone receptors in the endometrium. RESULTS: Endometrial thickness was increased after both treatments, although endometrial histology appeared atrophic in most biopsies. A circulating dose-response of serum progesterone levels was observed from the first to the 12th week of PVR use. In the high-progesterone-dose group, the scarce presence of Ki-67 and hormone receptors reflected the predominant action of progesterone in endometrial glands and stroma, in parallel with a lower tissue concentration of progesterone in this group. CONCLUSION: The PVR appears to be a promising method of administering natural progesterone to postmenopausal women treated with estrogen. Estradiol levels corrected the menopausal symptoms, as expected, and the presence of atrophic endometrium in the majority of women indicated that both doses of progesterone oppose the stimulatory estradiol effects, although the percentage of proliferative tissue was not negligible in both groups.

Effectiveness of different estrogen pulses in plasma for accelerating ovum transport and their relation to estradiol levels in the rat oviduct.

Elevations of circulating estradiol (E2) levels due to administration of exogenous E2 accelerate embryo transport through the genital tract in pregnant rats. This study relates oviductal embryo transport to tissue E2 levels associated with blood E2 oscillations of differing profiles. Plasma E2 pulses differing in rate of increase, amplitude, and duration were achieved through various schedules of iv and sc E2 administration. Rats on the first day of pregnancy received a total dose of 5 micrograms 17 beta-E2 by short (10-15 min) or long (200-300 min) term iv infusions. Some animals were used to monitor blood and tissue levels of E2 (oviduct and diaphragm). Others were killed 24 h after treatment to assess number of embryos recovered. Fast iv infusions caused brief, high amplitude (greater than 1000 pg/ml) E2 oscillations which were ineffective in eliciting accelerated embryo transport. The longer iv infusions produced lower but sustained elevations of circulating E2 levels comparable to those achieved by sc administration and were associated with accelerated embryo transport. The oviductal E2 concentration during and after a short iv infusion was never lower than that associated with a sc injection. The lack of response to a brief, high amplitude increase in circulating E2, therefore, could not be accounted for by decreased tissue content of the hormone. These results indicate that when the total mass of E2 administered is kept constant, the magnitude of embryo transport acceleration is positively correlated with the duration and negatively correlated with the amplitude and/or slope of increase in circulating estrogen. Since different tissue content of E2 does not account for the response or no response observed it follows that the geometry of E2 oscillations in plasma has a signal value for the target cells which acts independently from the bioavailability of the hormone.

Inhibition of atrial natriuretic peptide excretory action by bradykinin.

We examined whether the excretory effect of atrial natriuretic peptide could be antagonized by intravenously administered bradykinin or by elevated endogenous kinin levels attained during converting enzyme inhibition. Urinary volume and sodium and potassium excretion were determined every 20 minutes in female, anesthetized Sprague-Dawley rats (weight, 0.19 to 0.22 kg) infused with 10 microL/min isotonic glucose. In some experiments, urinary cGMP content was measured by radioimmunoassay. Two intravenous boluses of 209 pmol (0.5 micrograms) atrial natriuretic peptide were given before and after the injection of test substances, and the response ratio was used to quantify inhibition. Single injections of 94.3 or 142 pmol (100 or 150 ng) bradykinin, 3 minutes prior to atrial natriuretic peptide, inhibited the excretion of water, sodium, and potassium by 70%, 75%, and 50%, respectively. Larger (236 to 472 pmol) or smaller (23.6 to 47.2 pmol) bradykinin doses were ineffective. None of the bradykinin doses tested affected basal urinary output, systemic pressure, or the modest depressor effect of atrial natriuretic peptide. The anti-atrial natriuretic peptide effect of bradykinin was completely prevented by the kinin receptor antagonist Hoe 140. Converting enzyme inhibition with ramipril (96 nmol IV) also blunted atrial natriuretic peptide diuresis and natriuresis by 70% and reduced urinary cGMP excretion by 50%. These effects of ramipril were mediated by endogenous kinin accumulation, since they were abolished by pretreatment with Hoe 140. It is concluded that intrarenal kinins modulate the renal actions of atrial natriuretic peptide, and at a precise concentration bradykinin strongly antagonizes atrial natriuretic peptide by preventing its transduction mechanism.

Inhibition of atrial natriuretic peptide-induced natriuresis by plasma hydrolysates containing pepsanurin.

The specificity of antidiuretic actions of pepsanurin, a peptidic fraction obtained by pepsin hydrolysis of plasma, was studied in anesthetized rats and in isolated perfused rat kidneys. Pepsanurin was obtained from fresh dialyzed human plasma digested with pepsin (2,400 units/ml, 18 hours at 37 degrees C, pH 2.5), deproteinized (10 minutes at 80 degrees C), and centrifuged. In the rat, intraperitoneal injections of pepsanurin (0.5 ml/100 g body wt) significantly inhibited the effects of an intravenous bolus of atrial natriuretic peptide (ANP) (0.5 micrograms) on water, sodium, and potassium excretion without altering systemic blood pressure. In addition, pepsanurin abolished the peak in glomerular filtration rate and reduced the ANP-induced rise in fractional sodium excretion. Pepsanurin also inhibited the natriuretic effects of amiloride (10 micrograms/100 g body wt i.v.) without changing glomerular filtration rate, but it did not inhibit the potassium-retaining effect of amiloride. In contrast, pepsanurin had no effect on basal urinary excretion, and it did not affect the diuretic response induced by furosemide (doses of 25, 50, or 100 micrograms i.v.). Control peptidic hydrolysates prepared from human plasma preincubated 48 hours at 37 degrees C (PIPH), bovine albumin (BSAH), or human albumin did not inhibit ANP, amiloride, or furosemide. In perfused kidneys, pepsanurin significantly and reversibly reduced sodium and water excretion. Furthermore, pepsanurin, but not PIPH or BSAH, blocked the natriuretic and diuretic effects of ANP. These results support the existence of a specific plasma substrate able to release a peptide or peptides that counteract distal tubule diuresis and natriuresis by an intrarenal mechanism.

Late luteal phase administration of RU486 for three successive cycles does not disrupt bleeding patterns or ovulation.

RU486, a 19-nor steroid, binds with high affinity to the receptors for progesterone and glucocorticoids, blocking the actions of these hormones on their target tissues. We conducted studies to determine whether RU486 administered at the end of the luteal phase would disturb the menstrual rhythm, ovulation, or hormonal parameters in the treatment and post-treatment cycles. The first study was done in six surgically sterilized women during two consecutive cycles. RU486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-(1-propynyl)estra-4,9-dien-3-one; 100 mg/day] was given for 4 consecutive days, commencing on days 23-27 of the first cycle. Menstrual bleeding occurred by the second day of RU486 administration in all women and was indistinguishable from their usual bleeding pattern. The onset of this bleeding was advanced by RU486 administration, since it entailed shortening of the luteal phase with prolongation of the following follicular phase. Serum LH, FSH, estradiol, and progesterone levels were normal in five of the six women in both the treatment and posttreatment cycles. The second study was conducted in 10 women who were not exposed to the risk of pregnancy. RU486 (100 mg/day) was given for 4 consecutive days, commencing 4 days before their expected menses for 3 successive cycles, preceded and followed by 2 placebo-treated cycles. Bleeding patterns were indistinguishable during the RU486 and placebo cycles. Late luteal phase administration of RU486 consistently produced menstrual bleeding within 1-3 days of drug administration. Daily early morning urinary LH excretion in 6 women and estrone glucuronide and pregnanediol glucuronide excretion in 5 women during both placebo and RU486 cycles were consistent with luteinization, suggesting ovulation and appropriate corpus luteum function. We conclude that RU486 has no major effect on menstrual cycle events if given at the time of the natural progesterone withdrawal that occurs before menses in nonpregnant women.

Kinin B2 receptors mediate blockade of atrial natriuretic peptide natriuresis induced by glucose or feeding in fasted rats.

We have shown previously that the kininogen-derived peptides bradykinin, prokinins, and PU-D1, given intravenously or into the duodenal lumen, block the atrial natriuretic peptide (ANP)-induced diuretic-natriuretic effect in fasting, anesthetized rats infused with isotonic glucose. HOE-140, an inhibitor of bradykinin B2 receptors, completely suppresses this ANP blockade. When intravenous glucose infusion is omitted, the above-described inhibition of ANP does not take place. Therefore, to clarify the role of glucose and/or feeding in this phenomenon, we used fasted, anesthetized rats to test how the ANP excretory response was affected by (1) short-term feeding before anesthesia, (2) 1 mL of isotonic glucose introduced into the stomach, and (3) the interaction of HOE-140 with these treatments. In addition, we tested the effects of 1 mL of intragastric glucose administration and HOE-140 on urinary excretion in awake rats. In anesthetized rats, both glucose administration and feeding significantly inhibited the diuretic-natriuretic effect of ANP for up to 90 minutes. Similarly, intragastric glucose delayed spontaneous sodium and water excretion for 90 minutes in awake rats. In all 3 cases, pretreatment with HOE-140 (2.5 microg IV) fully prevented the inhibition of ANP excretory action, ruling out osmotic effects as the cause of reduced diuresis. These results indicate that the presence of glucose in the digestive tract triggers an inhibitory effect on ANP renal actions that requires activation of kinin B2 receptors, providing strong support to our hypothesis that during the early prandial period, gastrointestinal signals elicit a transient blockade of renal excretion with a mechanism involving the kallikrein-kinin system.

Urinary kallikrein and plasma renin activity in normal human pregnancy.

Urinary kallikrein excretion (UK), plasma renin activity (PRA), and 24-hour urine volume, sodium, and potassium excretion rates were determined sequentially in 16 normal pregnant women. Throughout gestation, UK was significantly elevated as compared to values obtained in 13 control women (1466 +/- 152 vs 375 +/- 90 U/g creatinine). The highest level was observed in Period 2 of gestation, corresponding to Weeks 17 to 24. PRA was also significantly elevated during pregnancy (11.97 +/- 1,35 vs 1.06 +/- 0.90 ng/ml/hr), with the highest level in Period 2. Mean 24-hour urine volume, sodium, and potassium excretion rates were significantly higher during pregnancy. Nor correlation was found between UK and: PRA, urine volume, and sodium and potassium excretions. These findings indicate a consistent activation of the renal-kallikrein-kinin system during pregnancy. We postulate that this vasodilator system might play a role in the maintenance of normotension in pregnancy, counteracting tha effect of the renin-angiotensin-aldosterone system.

Circadian variation of basal plasma prolactin, prolactin response to suckling, and length of amenorrhea in nursing women.

The circadian pattern of plasma PRL levels and the PRL response to suckling were examined at various times during the first postpartum year and related to the length of lactational amenorrhea. Ten healthy women whose infants were breast-fed exclusively and who were amenorrheic 3 months postpartum were studied 3, 6, and 9-11 months postpartum. The women and their babies were admitted to a metabolic unit for 48 h. On the second day, blood samples were drawn at 2-h intervals for 26 h starting at 0800 h and also 10 and 30 min after the initiation of six of the nursing episodes. During the three postpartum periods, there was a circadian rhythm of basal plasma PRL concentrations; the peak concentrations occurred between 2400-0600 h. Suckling induced a significant rise in plasma PRL levels at all hours except 0800 h. There was a positive correlation between the duration of the nursing episode and the suckling-induced PRL increase at 30 min. Both the basal plasma PRL levels and the PRL responses to suckling diminished with time after delivery. This trend was less evident at 0400 h and was not fully explained by changes in the nursing pattern. The five women in whom menstrual cycles resumed before day 180 postpartum had lower basal and suckling-induced plasma PRL levels than the women who had amenorrhea for a longer period. This difference was present in the third month, when all women were amenorrheic and fully nursing and when the frequency and duration of nursing episodes and infant growth rates were similar. The results indicate that comparable nursing patterns may be associated with different plasma PRL levels, which are associated with different lengths of lactational amenorrhea. An early difference in the sensitivity of the breast-hypothalamus-pituitary system to suckling may explain the differences in the duration of lactational amenorrhea, which are not dependant on the breastfeeding pattern. The magnitude of the PRL response to suckling may predict the likelihood of recovering ovarian function during lactation.

A peptide released by pepsin from kininogen domain 1 is a potent blocker of ANP-mediated diuresis-natriuresis in the rat.

A 20-amino acid peptide, KYEIKEGDCPVQSGKTWQDC (PU-D1), released by pepsin hydrolysis of LMW kininogen domain 1 was tested for its ability to antagonize the diuretic and natriuretic effect of ANP(103-125) in anesthetized rats. A single dose of 10.8 or 21.6 pmol (25 or 50 ng) PU-D1 given intravenously or into the duodenal lumen suppressed the diuresis-natriuresis induced by 209 pmol (500 ng) ANP by 43% to 59% and 69% to 96%, respectively. None of the doses tested (2.16 to 432 pmol, 5 ng to 1 microg) modified systemic blood pressure. Strikingly, a single IV dose of 10.8 pmol PU-D1 blocked the action of ANP for more than 3 hours. ANP blockade by PU-D1 was annulled completely by the bradykinin (BK) B2 receptor inhibitor Hoe 140. On a molar basis, PU-D1 is more effective than BK and kinins of 15, 16, and 18 amino acids for blocking the ANP-mediated diuresis-natriuresis. As with BK and other kinins, the inhibitory effect of Pu-D1 on ANP is obtained only within a small range of picomol doses. A single dose of 2.16 or 4.32 pmol PU-D1 or 47 pmol (50 ng) BK is ineffective against ANP if injected alone. However, when both substances are administered concomitantly at these subthreshold doses, they totally suppress ANP-induced diuresis-natriuresis. These results raise the question of whether PU-D1, released from kininogen domain 1, either alone or associated with BK, may interact with ANP in the regulation of urinary water and electrolyte excretion in physiological and pathological conditions.

The secretion of progesterone during the periovulatory period in women with certified ovulation.

A pre-LH peak rise of progesterone in peripheral blood has been found in 13 normal cycling women whose ovulation was confirmed by biopsy of the corpus luteum through serial determination of progesterone and LH performed every 8 h during the periovulatory period. The progesterone rise began as an average 22 h (16-40 h) prior to the LH peak. The maximal preovulatory rise took place 9.6 h (0-24 h) before the LH zenith, remaining low for approximately 17 h when an abrupt rise of progesterone took place. The progesterone peak was detected in the morning samples in 11 of 13 patients studied. The progesterone rise was always followed by an LH peak and the highest peak of progesterone was trailed by the highest LH peak in all the patients except one.

Early difference in the endocrine profile of long and short lactational amenorrhea.

The endocrine profiles associated with long and short lactational amenorrhea were assessed in a longitudinal study in which morning blood samples were drawn in 48 women from the first postpartum month until the recovery of ovulation and in a cross-sectional study in which the samples were drawn throughout 24 h at the end of the third postpartum month in 10 fully nursing and amenorrheic women. PRL, LH, FSH, estradiol (E2), progesterone, cortisol, and dehydroepiandrosterone sulfate were measured. In both studies we detected a smaller PRL increase in response to suckling (P less than 0.001) and higher E2 levels (P less than 0.001) in nursing women who ovulated within 6 months postpartum compared to those in women who did not. Such differences were observed early after delivery when all women were fully nursing and amenorrheic. These results suggest some probable sources of variability in the duration of lactational amenorrhea in our population. The greater PRL response to suckling associated with longer amenorrhea may be due to higher sensitivity of the breast-hypothalamus-pituitary system or a stronger suckling stimulus in this group. Differences in plasma E2 levels between longer and shorter periods of amenorrhea may reflect dissimilar endogenous production, intake, or clearance of estrogens.

Growth pattern of selected urban Chilean infants during exclusive breast-feeding.

This report describes the growth pattern of healthy, low middle and low socioeconomic class Chilean infants during exclusive breast-feeding. Two-hundred forty-two infants who were on exclusive breast-feeding at day 30 postpartum entered the study. Of these, 59% were fully nursing at 6 months and grew at a normal rate without receiving either supplementary milk or nondairy food. Supplementary feedings were administered in 27% of cases because of suspected primary inadequate milk output and in 14% of cases for other reasons such as pregnancy, illness, maternal work, or self-prescription. Full nursing provided the highest rate of weight increase during the first 3 months of life and a greater weight gain for boys than for girls up to the age of 6 months. Gastrointestinal pathology, malnourishment, or hospitalization were rare events in this population. It is concluded that maternal milk alone, if produced in sufficient amounts, can maintain normal growth up to the 6th month of life. The study supports the choice of exclusive breast-feeding on demand plus child growth monitoring up to 6 months over routine prescription of supplements at earlier times particularly where supplement administration fails to meet individual requirements.

PIP: This report describes the growth pattern of healthy, low middle and low socioeconomic class Chilean infants during exclusive breastfeeding. 242 infants who were on exclusive breastfeeding at day 30 postpartum entered the study. Of these, 59% were fully nursing at 6 months and grew at a normal rate without receiving either supplementary milk or nondairy food. Supplementary feedings were administered in 27% of the cases because of suspected primary inadequate milk output and in 14% of cases for other reasons such as pregnancy, illness, maternal work, or self prescription. Full nursing provided the highest rate of weight increase during the 1st 3 months of life and greater weight gain for boys than for girls up to the age of 6 months. Gastrointestinal pathology, malnourishment, or hospitalization were rare events in this population. It is concluded that maternal milk alone, if produced in sufficient amounts, can maintain normal growth up to the 6th month of life. The study supports the choice of exclusive breast feeding on demand plus child growth monitoring up to 6 months over routine prescription of supplements at earlier times particularly where supplement administration fails to meet individual requirements.

Effects of 4-hydroxyandrostenedione and exogenous testosterone on blood concentrations of oestradiol and oviducal embryo transport in the rat.

The effect of decreasing oestrogen secretion on the oviducal migration of embryos was investigated in pregnant rats. The reduction of oestradiol production was achieved by administration of the aromatase inhibitor 4-hydroxy-4-androstene-3,17-dione (4-OH-A) at various times after coitus. When 4-OH-A was administered from days 2 to 5, nearly half the embryos were retained in the oviducts at midday on day 5 of pregnancy, in contrast with control animals in which all embryos were transferred to the uterus. Shorter treatments were less effective. The rate of secretion of oestradiol from the ovary on days 2-5 of pregnancy in control rats was low in the morning and high in the afternoon. Treatment with 4-OH-A from days 2 to 5 reduced the secretory surges of oestradiol in the afternoon by 77% without significantly changing the progesterone output. Systemic testosterone levels were significantly increased by this treatment. To assess whether changes in the transport of ova were due to an increase in testosterone concentrations the influence of exogenous testosterone on embryo transport and oestradiol production was tested. Testosterone administered by subdermal implants from days 2 or 3 to day 5 disturbed embryo transport in a manner similar to that of 4-OH-A. The longest period of testosterone administration decreased ovarian oestradiol production by 82% without changing the secretion of progesterone.(ABSTRACT TRUNCATED AT 250 WORDS)

Isolation and characterization of rat plasma glandular kallikrein.

A method has been developed to purify glandular kallikrein present in rat plasma by using Sepharose-Aprotinin affinity chromatography and elution of the enzyme with p-aminobenzamidine. The isolated enzyme liberated kinins from kininogen II of low molecular weight (sp. act. 14 ng kinins/min X mg) and p-nitroaniline (pNA) from the substrate S-2266 (sp. act. 1.23 nmoles pNA/min X mg); it was inhibited by aprotinin, benzamidine and rat urinary antikallikrein antibody but not by ovomucoid. In polyacrylamide gel electrophoresis, the enzymatic activities of the preparation were associated with two light protein bands of molecular weights equal to that of urinary kallikrein (35,000 daltons). Using this method, the recovery of [125I]kallikrein added to the plasma was 82-88%. The concentration of the enzyme in normal rat plasma was equivalent to 6.1 +/- 2.1 (S.D.) ng kallikrein/ml. The mean value found in nephrectomized rats was 20.0 +/- 6.3 (S.D.) ng kallikrein/ml. This increment was highly significant (P less than 0.001). Our results confirm the presence of glandular kallikrein in plasma which had been detected by other methods; they also demonstrate that the material purified from plasma is enzymatically active, suggesting that kallikrein may play a biological role in the control of blood circulation.

Renal kallikrein system, volemia, and renal hypertension.

Plasma, blood, and urine volumes, renal kallikrein, and arterial pressure were measured in control and renal hypertensive rats in order to study the role of the renal kallikrein system in regulating arterial pressure and its relation with the alterations in water handling observed in hypertension. A decrease in kallikrein content of the kidney (157 +/- 17 versus 236 +/- 16 ng bradykinin equivalents per gram of tissue in control rats) was associated with an increase in plasma volume (38.0 "/- 1.6 versus 32.0 +/- 0.9 ml/kg body weight in control rats) and an increase in urine volume (45.5 +/- 4.9 versus 20.3 +/- 1.6 ml/kg body weight per 24 hours in control rats). No linear correlation was found between these factors and the arterial pressure of hypertensive animals. These findings support the hypothesis that changes in renal kallikrein are more directly related to water and electrolyte metabolism than to the arterial pressure regulation. Our results also suggest an interaction between the kallikrein-kinin and the renin-angiotensin-aldosterone systems. The possible relations of both enzymatic systems to the regulation of arterial pressure and of water-electrolyte handling are summarized schematically.

Subdermal contraceptive implants.

Subdermal contraceptive implants involve the delivery of a steroid progestin from polymer capsules or rods placed under the skin. The hormone diffuses out slowly at a stable rate, providing contraceptive effectiveness for 1-5 years. The period of protection depends upon the specific progestin and the type of polymer. Advantages of progestin implants include long term contraceptive action without requiring the user's or provider's attention, low dose of highly effective contraception without the use of estrogen, and fertility is readily reversible after the removal of implants. The levonorgestrel implant Norplant R system is the only one that has been approved for distribution. The contraceptive efficacy of Norplant is the highest observed amongst the most effective methods with an annual pregnancy rate of 0.2 during the first and second year and 1.1 on the fifth year. Menstrual problems are the main reason for the discontinuation of Norplant and 9% of women stopped using it during the first year of treatment. Other implants are still under development trying to simplify the method by reducing the number of units and to introduce other progestins that may minimize side effects. Norplant-2 was designed to release the same dose of progestin from only two covered rods. Evaluation of 1400 women enrolled, indicates that over 2 years the cumulative pregnancy rate is below 0.5 per 100 women. There are three single implants under development: Nestorone, 3-Keto-desogestrel and Uniplant that are expected to be effective for 1-2 years. Phase II clinical trials with Nestorone have been completed and no pregnancies have been observed in 1570 woman-months of use. Bleeding irregularities occurred in 20-30% of the women but there were only four terminations because of bleeding problems. A multricentric study is ongoing with a newly designed 3-keto-desogestrel implant named Implanon, which releases approx. 60 micrograms/day of the hormone. The objectives of this study are to assess contraceptive efficacy, safety and acceptability of Implanon. Another multricentric study is ongoing with Uniplant, which releases nomegestrol acetate with a duration of action for only 1 year. The objectives of the trial are to study the endocrine profile of Uniplant users and to evaluate the efficacy and acceptability of the method.

PIP: Subdermal contraceptive implants deliver progestin from polymer capsules or rods placed under the skin. Diffusing slowly from the polymer containers at a stable rate, the hormone provides contraception for 1-5 years, with the period of protection conferred dependent upon the specific progestin and type of polymer employed. Once inserted, the device allows a woman to have sexual intercourse over a certain period of time without any significant risk of becoming pregnant. Protection is ensured with a low drug dosage and no estrogen, and fertility is readily reversible once the implants are removed. The levonorgestrel implant Norplant R is the only subdermal contraceptive implant system approved for distribution. Annual pregnancy rates using Norplant are extremely low. Menstrual problems are the main reason why women discontinue using Norplant. Research is ongoing to reduce the number of implanted units and to introduce other progestins which may minimize side effects. Norplant-2 was designed to release the same dose of progestin from only two covered rods. Nestorone, 3-Keto-desogestrel, and Uniplant are single implants under development which are expected to be effective for 1-2 years. Completed phase II clinical trials with Nestorone found no pregnancies in 1570 woman-months of use, although bleeding irregularities occurred in 20-30% of women. A multicenter study is ongoing with a newly-designed 3-keto-desogestrel implant named Implanon, as well as another multicenter study with Uniplant, an implant which releases nomegestrol acetate with a one-year duration of action.

Mechanism of action of progesterone as contraceptive for lactating women.

Progesterone vaginal rings releasing 5-15 mg/day were tested as a contraceptive for lactating women. Progesterone plasma levels achieved ranged from 10 to 20 nmol/L. Pregnancy rates at the end of the year were less than 1% and 39% in treated (n = 210) and untreated (n = 236) nursing women, respectively. Around 70% of treated and 30% of untreated women were amenorrheic at 8 months post partum. The endocrine profile during the first 8 months post partum was assessed in 36 treated and 28 untreated nursing women. Pre- and postsuckling prolactin (PRL) levels were measured at 1600 hr at fortnightly intervals and E2 determinations and ovarian ultrasound were performed twice a week. Prolactin increases in response to suckling and postsuckling PRL levels were higher, E2 levels were lower, and follicular growth was arrested at earlier stages in progesterone-treated than in untreated women. The pattern observed in progesterone-treated women was similar to that in prolonged lactational amenorrhea. This suggests that progesterone increases the sensitivity of the breast-hypothalamic-pituitary system to suckling and reinforces the mechanism of lactational infertility.

Anatomy and pathology of tubal pregnancy.

The prevalence of tubal pregnancy has increased markedly during the past decade. The reasons for this are obscure. A systematic gross and histopathologic study of 25 consecutive ectopic pregnancies has been performed using a clearing method not used previously for this purpose. In addition, the presence of the corpus luteum and its location in reference to the tubal pregnancy are documented. Results indicate that trophoblastic spread was predominantly intraluminal in 67% of cases. Intratubal hemorrhage, generally in parallel to trophoblastic spread, often led to marked tubal destruction. Histologic evidence of salpingitis was noted in only seven of 24 specimens (29%). The corpus luteum was contralateral to the ectopic pregnancy in five of 21 cases (23.8%). Clinical correlates and areas of future research are discussed. Results indicate that segmental resection of the tubal pregnancy is appropriate in selected cases.

Effect of particle size on time course of transport of surrogate ova through the rabbit oviduct.

The time-course of transport of plastic microspheres of 100, 200, 400, 800, and 1000 mu diameter through the rabbit oviduct was studied under various hormonal conditions. During estrus, the rabbit oviduct rapidly transports particles of 200 mu diameter to the uterus. After ovulation, the passage of these particles is delayed, first at the ampullary-isthmic junction, and then along the isthmus, perhaps influenced by a second site of resistance at the uterotubal junction. Particles of 100 mu diameter are not subject to these delays but pass rapidly to the uterus. Our data support the idea that the rapid passage of 100-mu spheres reflects a size-related inability of the resisting "gates" to limit their passage. Pharmacologic doses of estrogen act to prolong or increase the resistance to particle passage at the ampullary-isthmic junction and apparently also accelerate transport through the isthmus. Progesterone presumably increases the efficiency of the "gate" at the ampullary-isthmic junction, hastens transport through the isthmus, and seems to "open the gate" at the utero-tubal junction. Further experiments are required to prove or negate these inferences.