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Biomedical subjects

H B Croxatto

Publications and source records attributed to H B Croxatto.

At least 55 records · Page 3Linked to original sources
PubMed1996

Effects of a sequential regimen of mifepristone-medroxyprogesterone acetate on ovarian function, endometrial development and hormonal parameters.

The efficacy of a low dose of mifepristone, 5 mg/day for the first 15 days of the menstrual cycle, followed by medroxy-progesterone acetate (MPA), 10 mg/day for the next 13 days, for inhibiting ovulation was assessed in ten volunteers who were treated for three successive cycles. Hormonal determinations in blood and urine samples, ovarian ultrasonography and an endometrial biopsy taken on day 21-24 of the third treatment cycle were used to monitor the cycles. Ovulation was confirmed in 11 of the 30 treated cycles and, in these 11, the LH peak and follicular rupture occurred during MPA treatment periods. Out of 19 anovulatory cycles, 16 had no increase in progesterone levels and another 3 developed a luteinized unruptured follicle. Progestin administration induced secretory changes in the endometrium, but irregular or delayed development was found. Regular withdrawal bleeding occurred in all subjects. These data indicate that the sequential regimen can suppress ovulation while maintaining regular bleeding but increased efficacy is needed for phase II clinical trials.

Adult↗
PubMed1996

Mechanisms of action of intrauterine devices.

The major effect of all intrauterine devices (IUD) is to induce a local inflammatory reaction in the endometrium whose cellular and humoral components are released into the uterine cavity. This inflammatory reaction has a variable effect on the reproductive strategy of the species studied. For example, this foreign body reaction can be localized within the uterus of rodents; and in farm animals it can have striking extrauterine effects. Thus, the action of IUDs in humans cannot be discerned from animals. In humans, copper ions released from Cu-IUDs enhance the inflammatory response and reach concentrations in the luminal fluids of the genital tract that are toxic for spermatozoa and embryos. In women using the IUD, the entire genital tract seems affected, at least in part, because of luminal transmission of the fluids that accumulates in the uterine lumen. This affects the function or viability of gametes, decreasing the rate of fertilization and lowering the chances of survival of any embryo that may be formed, even before it reaches the uterus. Studies on the recovery of eggs from women using IUDs and from women not using contraception show that embryos are formed in the tubes of IUD users at a much lower rate compared with nonusers. This is believed to be the major action of IUDs. Therefore, the common belief that the major mechanism of action of IUDs in women is through destruction of embryos in the uterus (i.e., abortion) is not supported by the available evidence. In Cu-IUD users, it is likely that few spermatozoa reach the distal segment of the fallopian tube, those that encounter an egg may be in poor condition. Thus, the few eggs that are fertilized have little chance for development and their possibility for survival in the altered tubal milieu become worse as they approach the uterine cavity.

Animals↗
PubMed1996

Antiprogestins: mechanism of action and contraceptive potential.

Antiprogestins are characterized by substitutions at the 11 beta and 17 alpha positions of the steroid ring system and bind strongly to both progesterone and glucocorticoid receptors. Although they function predominantly as antiprogestins and antiglucocorticoids, on occasion they display progestin agonistic and even antiestrogenic properties. The most common clinical use of the antiprogestin mifepristone is to induce a medical abortion in the early stages of pregnancy. Progesterone maintains the endometrium, transforming it from a proliferative to a secretory state. It also facilitates the luteinizing hormone surge, which initiates ovulation. As a consequence, antiprogestins may also have contraceptive potential. Although antiprogestins do delay ovulation, this effect is inconsistent unless high doses are given, and under these circumstances, the antiprogestin effect is associated with unopposed estrogen action on the endometrium. Very low doses of antiprogestins do not affect hormonal secretion or ovulation or alter bleeding patterns, but they do have contraceptive potential by inducing profound alterations in endometrial morphology. Mifepristone is also a very effective and safe postcoital agent. This new class of pharmacological agents has numerous other gynecological and obstetrical indications, such as endometriosis, uterine myoma, and expulsion of the fetus in the case of fetal death in utero. Antiprogestins may also be used in the treatment of steroid-dependent tumors. There are also therapeutic implications consequent to their antiglucocorticoid properties.

Abortifacient Agents, Steroidal↗
PubMed1996

Sucking pressure and its relationship to milk transfer during breastfeeding in humans.

Breast sucking pressure has been only partially characterized in humans and its quantitative relationships with milk transfer and endocrine maternal responses are unknown. A method to record sucking pressure and milk transfer during complete sucking episodes is described. A tubing connected at one end to a pressure transducer was attached to the nipple so that the baby sucked both the nipple and the catheter during breastfeeding. The transducer's signals were fed into a commercial computer system designed to digitize and analyse physiological signals. A total of 27 recordings, 13 of which were from a single breast and 14 from both breasts were evaluated. Average values for the mean and maximum sucking pressures were -50 and -197 mmHg, respectively; the median intersuck interval was 0.7 s; and duration of the sucking episode was 7 min. Diverse sucking pressure patterns were observed due to different mixes of sucking bursts with steady sucking and stable versus decreasing pressure and frequency throughout each sucking episode. The amount of milk transferred to the baby was estimated from the difference in body weight immediately before and after each episode. Milk transfer from the second breast was 58% lower than from the first; this was associated with a significant decrease in grams of milk transferred per suck or per minute without significant changes in sucking pressure. The data suggest that there is a change in the maternal physiological response to sucking between the first and second breast. This report shows the feasibility of measuring the sucking pressure developed by human babies during complete nursing episodes, and offers great potential to explore the relationships between the physical parameters of sucking and maternal physiological responses, such as hormonal changes, milk yield and duration of lactational amenorrhoea.

Breast Feeding↗
PubMed1995

Clinical trial with Nestorone subdermal contraceptive implants.

The clinical performance and the in vivo release rate of a single 4-cm Nestorone subdermal implant were investigated. Implants manufactured by two different procedures were compared. Volunteers were 70 healthy women of proven fertility. Forty women provided blood samples twice a week in the pretreatment cycle and for 5-6 weeks at 6-month intervals during treatment. Additional control cycles (n = 31) were studied in 19 Copper T users. No pregnancy occurred in 1570 woman-months. Nestorone plasma levels (x +/- S.E.) declined from 112 +/- 8 to 86 +/- 3 pmol/L (Implant A) and from 145 +/- 8 to 57 +/- 5 pmol/L (Implant B) from the first to the 24th month. Progesterone levels were < 9.5 nmol/L in 166 (93%) of 178 blood samplings taken during treatment. Progesterone levels > 16 nmol/L were found in only 7 sampling periods (3.9%) in treated women and in 70 (98.6%) out of 71 control cycles. No ovulation occurred with Nestorone plasma levels above 105 pmol/L. No abnormal changes were observed in plasma lipoproteins or other clinical chemistry parameters during treatment. The implants were well tolerated. The most frequent complaint was the occurrence of irregular bleeding. Enlarged follicles found during pelvic examination in 8 subjects (11.4%) disappeared spontaneously in 10 days to 6 weeks. Implants were removed because of medical (n = 10, 14.3%) or personal reasons (n = 6, 8.6%) or at the 24th month of treatment (n = 54, 77.1%). The estimated average daily in vivo release rate of Nestorone was 45-50 micrograms/day. A single Nestorone subdermal implant affords efficient contraceptive protection during two years.

Adolescent↗
PubMed1995

Effects of intermittent antiprogestin RU486 combined with cyclic medroxyprogesterone acetate on folliculogenesis and ovulation.

The results of several studies have suggested an inhibitory effect of the antiprogestin RU486 on late stages of folliculogenesis and ovulation. To assess the feasibility of using this property to inhibit ovulation without losing cycle control, an intermittent administration of RU486 alternated with medroxyprogesterone acetate (MPA) was tested in a phase I study. RU486 at a dose of 50 mg/day was given on menstrual cycle days 9-11 and 27-29, and 10 mg/day of MPA was given on cycle days 17-26 for three consecutive cycles to six Finnish and five Chilean women. Blood samples were collected two to three times a week for serum progesterone and oestradiol assays in three treatment cycles. One control cycle and one post-treatment recovery cycle were also monitored by serum samplings. Ultrasonography was carried out to measure follicular diameters in the treatment cycles. In 29 of 32 cycles, bleeding commenced within 3 days after the last MPA pill intake. Out of 32 treatment cycles, 20 were without luteal activity (serum progesterone < 9 nmol/l). Although 12 treatment cycles showed luteal activity (serum progesterone > or = 9 nmol/l), a clear rupture of a pre-ovulatory follicle > 15 mm, verified by ultrasonography, was seen in only one treatment cycle. During the treatment cycles with luteal activity (serum progesterone levels > or = 9 nmol/l), serum oestradiol concentrations were significantly higher on cycle days 9-18 and significantly lower at the end of the cycle compared with the cycles without luteal activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Luteinizing hormone pulsatile release and the length of lactational amenorrhoea.

The pattern of luteinizing hormone (LH) pulsatile release and the mean concentrations of follicle-stimulating hormone, oestradiol and progesterone were studied in nursing and non-nursing women. Blood samples were drawn at 5 min intervals between 10:00 and 14:00 h and between 22:00 and 02:00 h at months 3-4, 5-6, 7-8 and 9-10 postpartum in nursing women and in the follicular phase in non-nursing women. In nursing women, mean LH concentrations at months 3-4 were significantly lower than in non-nursing cycling women only in the subgroup which subsequently experienced > 6 months of lactational amenorrhoea, although all were fully nursing with a similar suckling frequency. LH pulses in plasma were found at all times in nursing women. There were no significant differences in the frequency (about four pulses every 4 h), amplitude or duration of LH pulses related to the duration of amenorrhoea, nor did these parameters vary significantly between amenorrhoeic or cycling nursing women and non-nursing women. Nursing amenorrhoeic women exhibited a normal frequency of LH pulse well in advance of the resumption of the first post-partum menses, suggesting that mechanisms other than the suppression of the gonadotrophin-releasing hormone pulse generator intervened in the inhibition of ovarian function during lactation.

Adult↗
PubMed1995

Follicle stimulating hormone-granulosa cell axis involvement in the antifolliculotrophic effect of low dose mifepristone (RU486).

This study was designed to assess the involvement of follicle stimulating hormone (FSH)-granulosa and luteinizing hormone (LH)-theca axes in the antifolliculotrophic effect of mifepristone. Plasma gonadotrophins, including plasma LH bioactivity and pulsatility, oestradiol, testosterone and inhibin concentrations, and follicular growth were monitored in volunteer women treated with placebo or mifepristone in two consecutive cycles. Mifepristone was given either as a single dose of 5 mg (n = 7) when the leading follicle had reached a diameter between 12 and 14 mm, or as a multiple dose of 5 mg/day for 3 days, beginning when the leading follicle had reached a diameter between 14 and 16 mm (n = 5) or between 6 and 11 mm (n = 5). Following the single dose of mifepristone, follicular growth and the accompanying increase in plasma oestradiol were arrested at 12 and 36 h respectively without changes in gonadotrophin or testosterone serum concentrations. The 3 day regimen arrested follicular growth and oestradiol rise and decreased plasma inhibin concentrations when follicles were larger than 12 mm at the onset of treatment. These results indicate that the antifolliculotrophic action of mifepristone is associated with a selective compromise of the FSH-granulosa axis of dominant follicles that have passed a critical stage of growth.

Adult↗
PubMed1995

Ultrastructure of human cumulus oophorus: a transmission electron microscopic study on oviductal oocytes and fertilized eggs.

The aim of the present study was to assess the heterogeneity of cumulus cells that occurs in human cumuli associated with oviductal oocytes and fertilized eggs. Transmission electron microscopy was used to study the cumulus masses surrounding both unfertilized oocytes and fertilized eggs (a pronuclear and a 4-cell stage) recovered at different intervals after ovulation. The specimens were obtained by flushing the oviducts of normal cycling women who underwent surgical sterilization. The cumuli were expanded due to large and irregular intercellular spaces; small linear gap junctions were seen at cell contacts, whereas annular gap junctions were found only in the cytoplasm of some cells. Both types of junction were less abundant in fertilized specimens. Cells surrounding fertilized eggs projected numerous long, thin microvilli into the intercellular spaces. As a rule, the inner layer of the cumulus mass (corona cells) was composed of cells whose surface was relatively smooth. Cumulus cells showed oval nuclei with one or more nucleoli. The cytoplasm of most cells possessed abundant organelles typical of steroidosynthesis: (i) mitochondria with tubular or villiform cristae; (ii) a well-developed smooth endoplasmic reticulum; and (iii) electron dense lipid droplets often surrounded by a few concentric membranes of smooth endoplasmic reticulum and/or in close contact with microtubules and microfilaments. Microperoxisome-like structures were also present. After fertilization, an enhancement of the steroidosynthetic characteristics occurred in the outer layers of the cumulus mass, but not in the corona cells, which still appeared capable of protidosynthesis. Together, these morphological features support the hypothesis that the cumulus of oviductal oocytes and particularly of fertilized eggs, luteinizes like parietal granulosa cells, generating a steroid hormonal micro-environment in the oviduct which may affect fertilization and zygote segmentation. Cumulus cells showing spermiophagic activity, as well as activated macrophages, leukocytes and red blood cells, were also found in the cumulus mass. The macrophages may play a local role both by phagocytic activity and by modulating the steroid secretion of the neighbouring cumulus cells which occurs in the ovarian follicle and corpus luteum. In conclusion, the cumulus mass surrounding tubal oocytes and fertilized eggs appears to be a heterogeneous and dynamic system, in which the micro-environment for fertilization and early embryo development is provided by diverse cell populations in addition to the oviductal cells.

Adult↗
PubMed1995

Sperm migration through the female genital tract of the New World monkey Cebus apella.

This study was designed to characterize sperm migration in the female genital tract of Cebus apella. Forty-eight cycles of eighteen females mated during the periovulatory period were studied. Eggs were searched for and spermatozoa were counted in segmental flushings of the genital tract performed in situ 1-7 h, 19-31 h, or 45-56 h after coitus. Of 14 eggs recovered, 8 were fertilized, thus assuring a reasonable normality of prefertilization phenomena in both males and females. A downward gradient of several orders of magnitude in sperm numbers was recognized from cervix to ampulla, particularly over the first interval. The population in the cervix and uterus decreased progressively between the first and last interval. Spermatozoa were recovered from the ampulla as early as 1 h after mating. Different trends were observed in the isthmus and ampulla. From the first to the last interval, sperm numbers decreased in the ampulla, but not in the isthmus. The number of spermatozoa recovered from the ampulla of the ovulatory side 1-31 h postcoitum was higher in postovulatory than in preovulatory monkeys, while in the nonovulatory side, recovery was similar in the two conditions. This findings suggests that the passage of spermatozoa up to the site of fertilization is under local control and is synchronized with ovulation. The pattern of sperm migration that emerges from these data bears similarities to the pattern in nonprimate species as well as distinctive features. A unique feature in common with the pattern in human is the early establishment of a fairly abundant and persistent sperm population in the ampulla.

Animals↗
PubMed1995

Possible role of platelet-activating factor in embryonic signaling during oviductal transport in the hamster.

Hamster embryos enter the uterus in pregnant females nearly one day earlier than unfertilized eggs in cycling females. The hypothesis that a substance derived from eicosanoids is released by the embryos, but not by oocytes, to hasten their transport to the uterus was tested by examining the effects of indomethacin, nordihydroguaiaretic acid (NDGA), platelet-activating factor (PAF), and PAF antagonists on egg transport in the hamster. Administration of indomethacin had no effect on embryo transport, whereas administration of NDGA delayed the transport of eggs to the uterus in pregnant but not in cycling hamsters. The PAF antagonists TCV-309 and BN-52021 delayed significantly the transport of eggs to the uterus in pregnant animals, but not in cycling animals; i.e., they retarded the passage of embryos but not of oocytes to the uterus. Administration of PAF to cycling hamsters hastened the oviductal transport of ova. These data suggest that, in the hamster, the earlier passage of embryos to the uterus as compared to oocytes is mediated by PAF. Thrombocytopenia was detected in early-pregnant hamsters, and PAF-like activity was detected in spent media of two-cell through morula stage hamster embryos. These results suggest that preimplantation hamster embryos produce PAF-like activity that mediates embryonic signaling to the oviduct as well as pregnancy-associated thrombocytopenia.

Animals↗
PubMed1995

Neuroendocrine mechanisms of lactational infertility in women.

The current knowledge on the mechanisms of lactational infertility, discussed during a symposium of investigators in this subject, is reviewed. Three periods of lactation are examined: the first weeks postpartum, the period of extended lactational amenorrhea and the recovery of ovarian function. In the first postpartum weeks the inhibition of ovarian function is accounted by diminished pituitary response to GnRH, since exogenous GnRH fails to elicit a LH increase. Suckling can extend the period of ovarian inhibition for weeks, months or years, although it does not fully suppress pulsatile secretion of LH beyond the first weeks. Extended lactational amenorrhea is associated with low LH plasma levels, a great PRL increase in response to suckling, low basal E2 levels and a suppression of estrogen positive feedback. Decreased immunoreactive LH levels may result from partial suppression of the LH pulse generator and a smaller mass of GnRH released in each burst. The role of neurotransmitters, PRL and ovarian factors is discussed. After the recovery of ovulatory cycles suckling still has a residual infertility effect, associated to inadequate luteal function. The sources of variation among women and populations were recognized. Areas in which research is needed to improve the understanding of the mechanisms that sustain lactational amenorrhea are suggested.

Adult↗
PubMed1994

Effect of mifepristone on inhibition of ovulation and induction of luteolysis.

Mifepristone administration to women in the mid- or late follicular phase delays the luteinizing hormone (LH) surge and prolongs the follicular phase. Since the resumption of follicular growth commences following mifepristone cessation, the drug must be given either continuously or at repeated intervals in order to block ovulation. Using various regimens with or without exogenous progestins, ovulation was inhibited in the majority of subjects. However, this was not consistent and in several instances, LH surges and a rise in plasma progesterone were suggestive of ovulation and corpus luteum function. Therefore, mifepristone cannot be used as a contraceptive which will reliably inhibit ovulation. With low-dose mifepristone administration, alterations in endometrial morphology were characterized by a delay in maturation despite the presence of ovulation. This suggests that the endometrium displays a greater sensitivity to mifepristone than does the pituitary, a finding that may have important contraceptive implications. Late luteal-phase mifepristone administration to women who were not sexually active did not alter their menstrual rhythm, bleeding patterns or steroid and gonadotrophin concentrations. However, when used in unprotected women in the late luteal phase, mifepristone did not uniformly terminate all pregnancies. On the other hand, when used within 72 h of intercourse, mifepristone was as effective a post-coital agent as the standard high-dose oestrogen-progestin combination.

Abortion, Induced↗
PubMed1994

Effects of RU486 on the ovarian response of immature rats to pregnant mare's serum gonadotrophin or diethylstilbestrol.

The purpose of this study was to further investigate the role of progesterone in follicular development induced by pregnant mare serum gonadotrophin (PMSG) or diethylstilbestrol (DES), in pre-pubertal rats, using RU486 to prevent the receptor-mediated actions of progesterone. Intact or hypophysectomized 26-day-old rats received either a single injection of 10 IU PMSG i.p., or 2 mg DES s.c. daily for 3 days, with or without 0.8 mg RU486 s.c. daily for 3 days. Groups of rats were killed 51-96 h after the first injection. RU486 significantly increased the ovarian weight gain, the ovarian and circulating concentrations of progesterone, the concentrations of immunoreactive and bioactive LH and the number of ovulated oocytes in intact rats. RU486 did not affect the ovarian weight increase induced by PMSG or the ovulatory response following PMSG plus human chorionic gonadotrophin (HCG) in rats hypophysectomized 24 h before initiating treatment or in intact rats where ovulation was blocked with chlorpromazine. The ovarian weight gain, the development of antral follicles and the increments in tissue and plasma progesterone concentrations and luteinizing hormone (LH) plasma concentrations elicited by DES in intact rats, were further increased by concomitant treatment with RU486, whereas the ovarian weight increase and antral follicle development induced by DES were completely inhibited by RU486 in hypophysectomized rats. Follicles stimulated to grow by DES plus RU486, but not by DES alone, were capable of ovulating in response to HCG.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effect of the antiprogestin onapristone on follicular growth in women.

The effects of the antiprogestin onapristone on the menstrual cycle were assessed in surgically sterilized volunteer women. The steroid was given orally at the dose of 5, 15 or 50 mg/day, from day 5 to day 11 of the cycle. Ovarian ultrasonography and hormonal determinations in plasma and urine were used to monitor the pre-treatment, treated and post-treatment cycles. Onapristone, given at a dose of 5 mg/day, affected follicular growth inconsistently. The dose of 15 or 50 mg/day arrested follicular growth and oestradiol increase and delayed gonadotrophin surge, extending the length of the follicular phase in five of seven women in each group. After discontinuation of treatment the leading follicle resumed its growth and ovulation occurred as judged by the elevation of plasma progesterone, preceded in most but not all cases by an echographic image of follicular collapse. The ensuing luteal phases were not significantly altered in length or plasma progesterone concentration. Cortisol concentrations were unaffected and no serious side-effects were recorded. The antifolliculotrophic effect of onapristone demonstrated here, together with previous reports of similar activity of mifepristone in women, indicate that this may be a general property of compounds that interfere with progesterone receptor function.

Adult↗
PubMed1994

Increased sensitivity and accumulation of estradiol in the rat oviduct during early pregnancy.

We have previously reported that a single injection of estradiol-17 beta (E2) given on day 3 of pregnancy (P3) is far more effective for accelerating oviductal transport in the rat, than treatment given on day 1 (P1). In order to quantify this change, dose-response curves were established for six different doses of E2 (range 0.031 to 1.00 micrograms per animal) given on P1, P2 or P3. In addition, a possible mechanism was explored by comparing the plasmatic and oviductal levels of E2 between 30 and 180 min following treatment with E2 on P1 or P3. As the interval from ovulation to treatment was increased, the transport of a larger number of embryos was accelerated and a smaller dose was required. The minimal effective dose decreased 30-fold from P1 to P3, the oviducts accumulated 20% to 90% more E2 on P3 than on P1, tissue levels were 6- to 48-fold higher than plasma levels and the latter did not differ between P1 and P3. It is concluded that the oviduct exhibits increased sensitivity and responsiveness to E2 on P3 and this is associated with greater accumulation of the hormone in the organ, not attributable to higher E2 plasma levels.

Animals↗
PubMed1994

Comparison of the effect of hypothalamic neuropeptides upon luteinizing hormone secretion by cultured rat anterior pituitary cells.

Bovine median eminence contains a factor difference from gonadotropin-releasing hormone (GnRH) than increases basal luteinizing hormone (LH) secretion and potentiates GnRH-stimulated LH release. We compared the effect of hypothalamic neuropeptides on basal and GnRH-stimulated LH secretion using rat pituitary cells under static incubation conditions to determine if any of them mimics the LH-releasing activity no attributable to GnRH present in bovine median eminence extracts. Both, galanin and neurotensin (10(-9)-10(-5)) stimulated basal LH secretion in a dose-response manner. Galanin increased 3-4 fold and neurotensin doubled the basal LH secretion. The GnRH antagonist Nal-Glu 10(-6) M abolished the effect of 10(-7) M GnRH and 10(-5)M neurotensin, but did not block the LH-releasing activity of galanin. Leucin-enkephalin, beta-endorphin, substance P and neuropeptide Y (NPY) did not alter basal LH secretion. Neuropeptides produced three types of response on GnRH-stimulated LH release. First, leucine-enkephalin and beta-endorphin (10(-9)-10(-5) M) showed a dose-dependent inhibition of GnRH-stimulated LH release. At 10(-5) M the inhibition was complete with leucine-enkephalin and only 30% with beta-endorphin. Both were blocked by naloxone. Second, substance P showed an inverted U type response on GnRH-stimulated LH secretion. At 10(-9) M this peptide potentiated the action of GnRH. This effect decreased when the dose of substance P was increased to 10(-7) M and turned inhibitory at 10(-5) M when 10(-7) M GnRH was used. Third, galanin and NPY potentiated the effect of GnRH on LH secretion. Neurotensin had no effect on GnRH-stimulated LH release. In conclusion, rat gonadotrophs present diverse responses to neuropeptides at physiological concentrations, and -apart from GnRH-galanin is most likely the other factor present in bovine median eminence extracts that stimulates LH secretion. The data lend further support to a role of galanin in the control of LH secretion.

Animals↗