Horacio B. Croxatto

Studies on the duration of egg transport by the human oviduct: II. Ovum location at various intervals following luteinizing hormone peak

The location of ova in the genital tract between 24 and 144 hours following the LH peak was determined in 23 normal women. Nineteen eggs were found in the Fallopian tubes between 24 and 96 hours and five eggs were recovered from the endometrial cavity between 96 and 144 hours following the LH peak. According to the present data and considering that ovulation occurs in the human subject nearly 17 hours after the LH peak, it is concluded that the transport of unfertilized ova in women is characterized by a period of retention in the ampulla, which lasts approximately 72 hours, followed by rapid transit through the isthmus and appearance of the ovum in the endometrial cavity around 80 hours after ovulation.

Physiology of gamete and embryo transport through the fallopian tube.

A great deal is now known about the migration of spermatozoa within the female reproductive tract, and how they interact with the oocyte and achieve fertilization in a variety of species. The process involves a series of complex features. It is a mixture of active and passive transport and active migration, with drastic jumps in the numbers of spermatozoa that migrate beyond specific physiological checkpoints, and with interactions occurring between spermatozoa, epithelium and luminal fluid. A reservoir of spermatozoa forms, at a discrete location, to hold and liberate spermatozoa in a gradual fashion. After fertilization has occurred, zygotes are passively transported to the uterus by a series of closely coordinated mechanical events where activities of cilia and smooth muscle predominate. Passage of the embryo from oviduct to uterus is regulated and timed by ovarian hormones, signals associated with mating, and zygotic substances. The diverse and exquisite patterns and regulatory signals typical of sperm migration and ovum transport across many species provide fascinating examples of adaptations according with differing reproductive strategies in various mammals.

Postcoital treatment with levonorgestrel does not disrupt postfertilization events in the rat

Levonorgestrel (LNG), a progestin widely used for regular hormonal contraception, is also used for emergency contraception (EC) to prevent pregnancy after unprotected intercourse. However, its mode of action in EC is only partially understood. One unresolved question is whether or not EC prevents pregnancy by interfering with postfertilization events. Here, we report the effects of acute treatment with LNG upon ovulation, fertilization and implantation in the rat. LNG inhibited ovulation totally or partially, depending on the timing of treatment and/or total dose administered, whereas it had no effect on fertilization or implantation when it was administered shortly before or after mating, or before implantation. It is concluded that acute postcoital administration of LNG at doses several-fold higher than those used for EC in women, which are able to inhibit ovulation, had no postfertilization effect that impairs fertility in the rat.

Lactational amenorrhea and the recovery of ovulation and fertility in fully nursing Chilean women

The probability of experiencing the first postpartum bleeding, the first ovulation and the risk of pregnancy during exclusive breastfeeding was assessed in a selected group of urban Chilean women. Admission criteria included having had a normal pregnancy and a vaginal term delivery of a healthy infant and the desire to maintain breastfeeding for as long as possible. The risk of bleeding and the recovery of ovulation was assessed in 48 women selected for being amenorrheic and fully nursing at day 75 postpartum and their willingness to participate in the blood sampling protocol. The first bleeding and ovulation was experienced while fully nursing by 28% and 26% of these subjects, respectively, at day 180 postpartum. The probability of experiencing the first bleeding and the probability of pregnancy during full nursing were calculated for 236 women not contracepting who were enrolled during the first month postpartum. The cumulative probability of bleeding and of pregnancy was 52% and 9.4% at day 180 postpartum, respectively. The risk of pregnancy was less than 2% in the subset of amenorrheic cases. In this urban population selected for having the highest motivation and best breastfeeding performance, the association of breastfeeding with infertility was too weak to serve as an effective birth spacer, except for the period of lactational amenorrhea. When the first postpartum bleeding took place before the sixth postpartum month in fully nursing women, it had a good predictive value to indicate the onset of a higher risk period.

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.

Contraceptive efficacy of lactational amenorrhea in urban Chilean women

The contraceptive efficacy of breastfeeding was assessed in 236 healthy urban women who were followed at monthly intervals during the first postpartum year. Proportional hazard models were used to evaluate the influence of time postpartum, menstrual status and breastfeeding pattern upon the risk of pregnancy. Time and menstrual status had a highly significant effect on this risk. Those women who remained in amenorrhea had cumulative probabilities of pregnancy of 0.9% and 17% at 6 and 12 months postpartum, respectively. In those who recovered menstrual cycles, the risk rose to 36% and 55% at 6 and 12 months, respectively. Milk supplementation also increased significantly the risk when considered alone but not when time and/or menstrual status were included in the analysis. However, amenorrheic women who introduced bottle feeding, had a higher risk of pregnancy after 6 months postpartum than those who remained fully nursing. The analysis was unable to detect a significant influence of the nursing frequency. The results confirm that lactational amenorrhea is an effective contraceptive during the first six months postpartum. The first postpartum bleeding marks a great increase in the risk of pregnancy. Supplementation also increases the risk, particularly in amenorrheic women.

Estrogen Receptor, Cyclic Adenosine Monophosphate, and Protein Kinase A Are Involved in the Nongenomic Pathway by Which Estradiol Accelerates Oviductal Oocyte Transport in Cyclic Rats

Abstract This investigation examined the role of estrogen receptor (ER) on the stimulatory effect of estradiol (E2) on protein phosphorylation in the oviduct as well as on E2-induced acceleration of oviductal oocyte transport in cyclic rats. Estrous rats were injected with E2 s.c. and with the ER antagonist ICI 182u200a780 intrabursally (i.b.), and 6 h later, oviducts were excised and protein phosphorylation was determined by Western blot analysis. ICI 182u200a780 inhibited the E2-induced phosphorylation of some oviductal proteins. Other estrous rats were treated with E2 s.c. and ICI 182u200a780 i.b. The number of eggs in the oviduct, assessed 24 h later, showed that ICI 182u200a780 blocked the E2-induced egg transport acceleration. The possible involvement of adenylyl cyclase, protein kinase A (PK-A), protein kinase C (PK-C), or tyrosine kinases on egg transport acceleration induced by E2 was then examined. Selective inhibitors of adenylyl cyclase or PK-A inhibited the E2-induced egg transport acceleration, whereas PK-C or tyrosine kinase inhibitors had no effect. Furthermore, forskolin, an adenylyl cyclase activator, mimicked the effect of E2 on ovum transport and E2 increased the level of cAMP in the oviduct of cycling rats. Finally, we measured PK-A activity in vitro in the presence of E2 or E2-ER complex. Activity of PK-A in the presence of E2 or E2-ER was similar to PK-A alone, showing that E2 or E2-ER did not directly activate PK-A. We conclude that the nongenomic pathway by which E2 accelerates oviductal egg transport in the rat requires absolute participation of ER and cAMP and partial participation of PK-A signaling pathways in the oviduct.

Egg Transport in the Fallopian Tube

The transport of eggs from the site of ovulation to the site of implantation is a fundamental step of the reproductive process in the female. The fallopian tube effects the major part of this function and times the passage of eggs into the endometrial environment. As a result of different combinations of speed of progression and retention periods through the various regions of the oviduct, the pattern of transport differs from one species to another. The role of muscular contraction, ciliary movement and flow of secretions in the mechanisms of progression and retention are still poorly understood. Estrogens and progestins have a pronounced influence upon egg transport, but the responses to exogenous hormones are quite variable and depend mainly upon species, dose and time of administration. Species differences prevent from broader generalizations at this time and indicate the need for further comparative studies.

Studies on the duration of ovum transport by the human oviduct. III. Time interval between the luteinizing hormone peak and recovery of ova by transcervical flushing of the uterus in normal women.

This article deals with attempts to time the onset and duration of the ovums sojourn in the endometrial cavity of women. Recovery of the ovum from the uterus was attempted by means of transcervical flushing of the cavity 48 to 216 hours after the luteinizing hormone (LH) peak in plasma. A single flushing or repetitive flushings done at 24-hour intervals in the same cycle were performed in different subjects. With both modalities, the adverse effects were mild and few. Of 132 flushings done in 76 subjects, 90 were considered to be technically adequate from the point of view of recovering over 50% of the flushing volume. Twenty ova were recovered. Technically adequate flushings and adequate timing of the LH peak were accomplished in 39 cycles. In this group, 13 ova were recovered between 96 and 168 hours after the LH peak. The highest yield of ova per flushing was obtained from 120 to 168 hours with an average of 37% and a range of 25% to 50%. Limitations of the technique are discussed. Some uncertainties persist which prevent the drawing of definitive conclusions about how soon after the LH peak the egg enters the uterine cavity, how long it stays there, and what is the extent of individual variation. However, recovery rates at various times after ovulation agree with previous data derived from transfundal flushing and indicate that the ovum is usually transferred to the uterus between 96 and 120 hours after the LH peak is retained there for several days.

Relative contributions of anovulation and luteal phase defect to the reduced pregnancy rate of breastfeeding women

OBJECTIVEnTo evaluate the contribution of anovulation and luteal phase defects to lactational infertility.nnnDESIGNnProspective longitudinal follow-up.nnnSETTINGnOutpatient clinic.nnnSUBJECTSnForty-nine women fully nursing and amenorrheic on day 75 postpartum and 25 cycling, interval non-nursing women.nnnINTERVENTIONSnPlasma prolactin, luteinizing hormone, estradiol (E2), and progesterone (P) levels twice a week up to the second postpartum menses.nnnMAIN OUTCOME MEASURESnOvulation rate and endocrine profile of the menstrual cycles.nnnRESULTSnOvulation rates were 37% and 97% at 6 and 12 months postpartum; 67% of ovulations occurred in amenorrhea. The luteal phase was shorter, and E2 and P levels were lower in lactating women than in non-nursing women. These parameters were closer to normal in the second cycle than the first, in spite of active nursing. The risk of ovulation and pregnancy in amenorrhea was 27.7% and 0.9% at month 6 postpartum. After the first menses, these risks were 93% and 7%, respectively.nnnCONCLUSIONnThe abnormal endocrine profile of the first luteal phase offers effective protection to women who ovulate during lactational amenorrhea within the first 6 months after delivery. Later luteal phases are improved and women are at risk of pregnancy.