Ervin E. Jones

The effect of endometriosis on implantation : results from the Yale University in vitro fertilization and embryo transfer program

OBJECTIVE To investigate the effect of endometriosis on implantation. DESIGN Case-control study from Yale University IVF-ET program. PATIENTS Two hundred eighty-four consecutive IVF cycles were analyzed retrospectively. Patients with endometriosis only (n = 35; 89 cycles) were compared with an age-matched control group with tubal infertility (n = 70; 147 cycles) and also to a group with unexplained infertility (n = 15; 48 cycles). Data from the endometriosis group was analyzed further in subgroups of minimal-mild (43 cycles) and moderate-severe (46 cycles). RESULTS No difference was found in the number and the quality of oocytes retrieved and fertilization rates between the endometriosis, the tubal infertility, and the unexplained infertility groups. The quality and the number of embryos transferred in each group were comparable. A trend toward reduced pregnancy rate per transfer (14.8%) in the endometriosis versus tubal or unexplained infertility groups (25.7% and 23.3%, respectively) was observed. Implantation rate (gestational sac per transferred embryo) was significantly lower in the endometriosis versus the tubal infertility group (3.9% versus 8.1%; unexplained infertility group, 7.2%). Analysis of first cycles only across all groups revealed that the implantation rate also was significantly lower in the endometriosis versus the tubal infertility group (3.1% versus 9%; unexplained infertility group, 6.7%). Within the endometriosis group, although the pregnancy rate per cycle and per transfer were similar in subgroups, patients with minimal-mild endometriosis had the lowest implantation rate. CONCLUSION We conclude that, in patients with endometriosis, implantation rate is low. Abnormal implantation, which may be secondary to endometrial dysfunction or embryotoxic environment, is a factor in endometriosis-associated subfertility.

Monocyte chemotactic protein-1 expression in human preovulatory follicles and ovarian cells

There is a considerable population of macrophages (5-15% of the cells) within the human ovarian follicle at the time of ovulation. Macrophages are also present within the ovarian stroma, mostly near perifollicular capillaries. We hypothesized that macrophage migration in and around the preovulatory follicle is hormonally regulated and that regulation of macrophage migration occurs through local modulation of monocyte chemotactic protein-1 (MCP-1) that chemoattracts and activates monocytes/macrophages. In this regard, we investigated the expression and regulation of MCP-1 in human follicular fluid and in ovarian stromal and granulosa-lutein cell cultures. The concentration of MCP-1 in follicular fluid samples obtained from women prior to the administration of hCG was (n = 4) 90 +/- 27 (mean +/- S.E.) pg/ml; in samples obtained 12 h after the hCG administration it was (n = 3) 135 +/- 23 pg/mL; in follicular fluids obtained 34 h after the hCG administration it was (n = 126) 322 +/- 46 pg/mL (P = 0.007 vs. pre-hCG). The mean ratio of follicular fluid/serum MCP-1 levels was 4.18. There was a correlation between follicular fluid MCP-1 levels and follicular fluid or serum progesterone levels (r = 0.21, P = 0.02; r = 0.29, P = 0.03, respectively). MCP-1 mRNA and the protein were expressed in ovarian stromal and granulosalutein cells in culture and were increased by interleukin-1 alpha and tumor necrosis factor-alpha in a time- and concentration-dependent manner. LH/hCG induced higher levels of MCP-1 mRNA expression and protein production in both cell cultures. We propose that regulation of MCP-1 in ovarian stromal and granulosa-lutein cells by cytokines may play a role in the physiology of periovulatory events.

Estrogen effects on the tuberoinfundibular dopaminergic system in the female rat brain

Estrogen effects on tyrosine hydroxylase (TH), monoamine oxidase types A and B (MAO), and dopamine (DA) in microdissected regions of the hypothalamus, preoptic area and substantia nigra (SNR) of the female rat brain were investigated. Ovariectomized (OVX) young adult female rats were implanted with single silastic capsules containing 100% estradiol valerate (EV). Control rats received empty silastic capsules. Two weeks following capsule insertion, EV decreased TH activity and DA concentration in the arcuate nucleus (AN) while no significant changes in TH activity or DA concentration were observed in the SNR, ventromedial nucleus (VMN), suprachiasmatic nucleus, paraventricular nucleus, medial preoptic nucleus, or the periventricular preoptic nucleus. Although estrogen suppressed TH and DA in the AN, 2 weeks following removal of the estrogen containing capsules, TH activity and DA concentration were restored to control (OVX) levels. Suppression of MAO activity occurred in both the AN and the VMN of rats implanted with EV capsules and returned to OVX levels following the removal of the estradiol load. These results revealed that estrogen effects on TH and MAO activities and DA concentration in the midbrain are region specific and reversible; and that among the dopaminergic systems studied, estrogen effects on TH and DA are confined to the tuberoinfundibular dopaminergic system (TIDAS). Furthermore, these results support our hypothesis that estrogen is a key regulator of DA function in the TIDAS via effects on TH. The importance of these findings to the control of gonadotropin secretion and reproductive cyclicity is discussed.

Reproductive Function in Epilepsy

Summary: : The hypothalamic‐pituitary‐gonadal axis is a complex system within which both positive and negative feedback occur among its elements and higher brain systems. The occurrence of seizures and changes in the secretion of pituitary hormones can affect the feedback loop. Both seizures and antiepileptic drugs can affect the hypothalamic‐pituitary‐gonadal axis of males and females and cause changes in hormones and sexuality. Reproductive dysfunction has a social impact because of reduced fertility. Once conception occurs, live birth rates are not diminished. Prospective studies of men and women with epilepsy are needed.

Attitudes of IVF parents regarding the IVF experience and their children.

AbstractPurpose: to assess parental attitudes regarding the IVF experience, the IVF pregnancy, and issues associated with raising their IVF child(ren). Method: parents (184 couples) of IVF children born between 1982 and 1992 were mailed individual anonymous questionnaires. Results: (31%) parents responded: 62 mothers and 41 fathers. One hundred-three (41%) of the mothers felt that our staff could have been more helpful during their pregnancy. Half the women subjects (52%) stated that they wished they had contact with other IVF couples during pregnancy. Fifty-two percent of the mothers reported that IVF created special feelings of attachment to the child, causing some difficulty with their initial separation. This was comparatively less an issue for fathers, with only 19% reporting similar difficulties (X2=8.39, P<0.01). Ninety-eight percent of the subjects have told someone else about the IVF experience. Interestingly, 25% of the parents remained uncertain about whether they would tell the child. Sixteen couples (15%) had already told the child, and of the 57 (66%) who intended to tell the child later, they varied greatly in their views about which age would be appropriate (mean, 7.3 years; SD, 6.5 years; range, 2–21 years). Conclusions: The results suggest that women undergoing IVF might profit from greater contact with staff during pregnancy and, again, later when dealing with issues of separation. A substantial proportion of couples expressed some concerns about the issue of disclosure to the child and might profit from counseling when they feel the issue is current.

Baseline cyst formation after luteal phase gonadotropin-releasing hormone agonist administration is linked to poor in vitro fertilization outcome*

OBJECTIVE To investigate the prognostic significance of baseline ovarian cysts after luteal phase GnRH agonist (GnRH-a) administration for IVF-ET. DESIGN All nondonor IVF-ET cycles in one program in which luteal phase GnRH-a was administered between July 1993 and January 1994 were assessed for the formation of baseline ovarian cysts defined as a mean diameter > or = 15 mm. Outcome data from the IVF cycles were compared between patients with and without baseline ovarian cysts. RESULTS Of 78 IVF cycles, baseline cysts > or = 15 mm were noted in 26 cycles. Cycles in which cysts were formed were associated with significantly older patients with significantly higher baseline FSH values. Cycles in which cysts were present demonstrated fewer follicles, retrieved oocytes, and embryos. Cyst cycles also demonstrated a lower peak E2 level, implantation rate, and clinical pregnancy rate (PR) per initiated cycle (7.7% versus 32.7%). Cyst cycles also demonstrated a higher cancellation rate. Logistic regression modeling, accounting for age, confirmed significantly lower clinical PRs in cycles with a baseline cyst. CONCLUSIONS Baseline cyst formation after luteal phase GnRH-a administration is both a marker for poor responders and a reliable predictor of poor stimulation and low PRs in a given IVF-ET cycle.

Secretion of inhibin B during ovarian stimulation is decreased in infertile women with endometriosis

OBJECTIVE(S) To determine the levels and pattern of inhibin B secretion during ovarian stimulation in patients with endometriosis and to evaluate the correlation between inhibin B levels and variables of follicular and oocyte development. DESIGN Retrospective cohort study. SETTING IVF center. PATIENT(S) Women with endometriosis (n = 20) and tubal factor (n = 10) as the only cause of infertility. INTERVENTION(S) Inhibin B levels were measured during gonadotropin stimulation on day 1, days 8-11, day of hCG administration, and oocyte retrieval. MAIN OUTCOME MEASURE(S) Patterns and levels of inhibin B secretion were compared in the two groups. Other variables analyzed were age, days of gonadotropin stimulation and total ampules used, oocytes retrieved, and the fertilization and pregnancy rate. RESULT(S) Inhibin B levels and number of oocytes retrieved were significantly lower in patients with endometriosis than in the control group. Two patterns of inhibin B secretion were noted: It peaked in the midfollicular phase or on the day of hCG administration. In contrast, E2 levels peaked on the day of hCG administration. Inhibin B in the midfollicular phase in both groups correlated positively with number of oocytes retrieved. In addition, E2 and inhibin B levels in the midfollicular phase correlated positively. CONCLUSION(S) Decreased inhibin B secretion in patients with endometriosis suggests impaired granulosa cell function. Inhibin B may serve as an alternate marker to assess follicular development or to predict the number of oocytes retrieved.

The effect of Norplant on glucose metabolism under hyperglycemic hyperinsulinemic conditions.

OBJECTIVES To assess the impact of a levonorgestrel-releasing implant contraceptive (Norplant; Wyeth-Ayerst Laboratories, Philadelphia, PA) on glucose metabolism. DESIGN Prospective evaluation of insulin action and secretion in women under hyperglycemic hyperinsulinemic clamp conditions in the midfollicular phase before and 8 weeks after Norplant placement. SETTING Yale University Clinical Research Center. PARTICIPANTS Seven previously normally cycling, nonobese, nondiabetic women participated in the study. INTERVENTIONS Norplant insertion. MAIN OUTCOME MEASURES Basal levels of glucose and insulin, as well as glucose-mediated insulin secretion, glucose uptake, and tissue sensitivity to insulin were assessed using the hyperglycemic hyperinsulinemic clamp technique before and after Norplant insertion. RESULTS Norplant placement did not alter the fasting glucose or insulin levels. However, it was associated with a significant 37% increase in the first phase insulin response from a control level of 51 +/- 8 to 70 +/- 10 microU/mL (conversion factor to SI unit, 7.175), and a significant 48% increase in the second phase insulin response from 60 +/- 5 to 89 +/- 8 microU/mL. In association with this increase in insulin levels after Norplant insertion, total mean body glucose uptake (M) increased from 8.08 +/- 0.91 to 9.53 +/- 0.95 mg/kg per minute. However, when expressed as the total body glucose uptake per unit of insulin, the M:I ratio (a measure of tissue sensitivity to insulin) decreased significantly from a mean of 0.12 +/- 0.02 to 0.10 +/- 0.01 mg/kg per minute per microU/mL. CONCLUSION Although Norplant insertion does not alter basal glucose and insulin levels, tissue sensitivity to insulin under hyperglycemic hyperinsulinemic conditions is decreased after Norplant insertion.

Ovarian cysts decrease the success of controlled ovarian stimulation and in vitro fertilization.

Forty cystic structures, 16 to 60 mm, of probable ovarian origin were found in 126 cycles during an ultrasound scan on day 3 of a cycle in which in vitro fertilization was planned. The response of these patients to exogenous gonadotropin stimulation, oocyte capture, fertilization, cleavage, and pregnancy was studied. Patients with cystic change had significantly lower peak estradiol (E2) levels. Pregnancy rates were lower, but not significantly so. Those patients with structures 16 to 29 mm had more cycles canceled due to precipitous drops in E2, consistent with an untimely surge of luteinizing hormone. Patients with structures 30 to 60 mm had increased numbers of cycles with poor response to stimulation. The importance of an early follicular phase ultrasound scan is stressed, and the management of ovarian cysts in this patient population is discussed.

Growth-Regulated α Expression in Human Preovulatory Follicles and Ovarian Cells

PROBLEM: Around the time of ovulation the number of neutrophils increases in the theca of the leading follicle. We hypothesized that growth‐regulated a (GROα), a neutrophil chemoattractant/activating factor, may be a modulator of periovulatory neutrophil chemotaxis.