Steven T. Nakajima

A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis

This study was initiated to test the hypothesis that treatment with clomiphene citrate (CC) and intrauterine insemination (IUI) results in increased fecundity when compared with periovulatory intercourse in couples with either unexplained infertility or surgically corrected endometriosis. Sixty-seven couples entered a randomized, prospective trial comparing CC/IUI with observation. During the study, there were 14 pregnancies in 148 treated cycles (fecundity = 0.095) compared with 5 pregnancies in 150 untreated cycles (fecundity = 0.033). Using life-table analysis and the log-rank test, the difference in fecundities was statistically significant. Pregnancy outcome was not significantly different between the two groups. When comparing conception with nonconception cycles during treatment, no differences between the size of the lead follicle or the number of dominant follicles was detected. We conclude that treatment with CC/IUI improves fecundity in couples with unexplained infertility or surgically corrected endometriosis.

Female genital anomalies affecting reproduction

OBJECTIVE A multitude of female congenital anomalies are uncommon. However, their impact on reproduction can be profound. The aim of this review is to remind the practicing physician of the clinically relevant embryology and summarize the studies that look at the impact of such various anomalies on a womans fecundity. We review particular surgical therapies that possibly may improve fertility in such women. DESIGN Review and critique of available studies in which particular surgical therapies were done and whether they truly improved fertility in these women with congenital reproductive anomalies. RESULTS Clear evidence demonstrates that uterine septum resection is effective in women with demonstrated recurrent pregnancy losses. Arcuate uterus has little impact on reproduction. Other studies fail to definitively show that surgical correction will improve pregnancy retention or fertility except for specifically indicated clinical scenarios. CONCLUSIONS The practicing reproductive specialist should have working knowledge of evidence-based therapeutic options for women with reproductive congenital anomalies. A summary chart has been devised to clearly associate embryologic structures with normal adult derivative as well as anomalous structures.

Current methods of tubal patency assessment

OBJECTIVE To evaluate the scientific literature on current methods of uterine cavity and tubal patency assessment. DESIGN Review of literature and appraisal of relevant articles using MEDLINE, OVID, EMBASE, and Cochrane on-line databases. RESULT(S) Current pelvic imaging subfertility investigations are compared with the gold standard laparoscopy. The technical aspects, associated risks, potential advantages, and weighted utility of each screening study are discussed. A comprehensive analysis of the clinical evidence regarding the safety, tolerance, and accuracy of hysterosalpingo-contrast sonography compared with alternative screening studies and/or laparoscopy is reviewed. CONCLUSION(S) Increasing evidence supports the more recently described hysterosalpingo-contrast sonography procedure as an acceptable screening study for the subfertile patient with the potential advantage that it is a comprehensive evaluation, methodologically simple, cost effective, and time efficient.

Alterations in humoral immune responses associated with recurrent pregnancy loss

OBJECTIVE To investigate the reactivity of maternal antibodies with endometrium-derived antigens and to correlate their association with recurrent pregnancy loss (RPL). DESIGN Prevalence study. SETTING Academic research center. PATIENT(S) Nulliparous women (n = 10), women with RPL (n = 15), pregnant women (n = 8), and multiparous women with a normal obstetric history (n = 20). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Reactive antibodies were analyzed by Western immunoblot techniques and quantitated by densitometry. RESULT(S) Antibodies from women with RPL and multiparous women recognized antigens ranging from 10-120 kd on normal endometrium and endometrial tumors. Antibodies from most women with RPL (10/15) and from multiparous women (15/20) recognized 65-kd and 80-kd proteins in normal endometrium. Antibodies from women with RPL recognized 21-kd and 28-kd antigens (12/15 and 13/15, respectively) in endometrial tumors at a significantly greater rate (than did antibodies from multiparous women (5/20 and 8/20, respectively). Women with RPL had significantly lower levels of asymmetric IgG compared with controls. CONCLUSION(S) Recurrent pregnancy loss may be linked with the failure to elicit asymmetric IgG and a unique immunologic recognition of endometrial antigens.

Dysregulation of leptin and testosterone production and their receptor expression in the human placenta with gestational diabetes mellitus.

Whether the placenta contributes to some of the abnormal hormonal profiles in gestational diabetes mellitus (GDM) pregnancies and whether GDM affects placental endocrine signaling pathways are yet to be established. The objective of this study was to investigate differences in the expression of the placental steroid and peptide hormone synthesis-related factors, enzymes and their receptors between normal and GDM pregnancies. Nine term placentae from GDM pregnancies and twelve from healthy pregnancies were collected. The results of immunohistochemistry, Western blotting and semiquantitative RT-PCR indicated that mRNA and protein levels of leptin, leptin receptors, androgen receptor and FGF2 were significantly higher in the GDM placentae than non-GDM placentae; while NRIH3, NRIH2, StARD3, CYP11A1, HSD3B, HSD11B, HSD17B, ERalpha, ERbeta, progesterone receptor, FGF receptor-2, insulin receptor-alpha and -beta showed no differences. Interestingly, Western blotting and immunohistochemistry revealed that aromatase protein concentrations in the GDM placentae were significantly reduced without a change in mRNA levels. Moreover, androgen upregulated FGF2 expression in the placental villous explants. These findings suggest that the placentae of GDM pregnancies contribute to elevated testosterone and leptin levels due to a decrease in the conversion of testosterone to estrogens and to an increase in leptin production. The androgen and leptin signaling pathways may be over-activated by the presence of excessive ligands and overexpressed receptors in GDM placentae. Dysregulation of these two endocrine networks may contribute to placental abnormalities eventually increasing the frequency of maternal and fetal complications associated with GDM.

Urinary follicle-stimulating hormone peak as a biomarker for estimating the day of ovulation

OBJECTIVE To evaluate urinary follicle-stimulating hormone (FSH) as a biomarker for the day of ovulation. DESIGN Prospective observational study. SETTING Clinical research center. PATIENT(S) Thirteen women were monitored with measurements of serum and urinary hormones and ovarian ultrasonography during 20 menstrual cycles. Data on urinary hormones and ultrasound evaluations from a total of 65 menstrual cycles from 42 women were analyzed. INTERVENTION(S) Blood and/or urine samples were collected daily. Daily transvaginal ultrasonography was used to detect follicular collapse. MAIN OUTCOME MEASURE(S) LH, FSH, and E(2) were measured in serum. FSH, estrone conjugates (E1C), and pregnanediol-3-glucuronide (PdG) were analyzed in urine. The day of luteal transition (DLT) was calculated using two algorithms. RESULT(S) In 20 cycles, the urinary FSH peak was closer to the day of follicular collapse (-0.85 days) than was the peak day of serum E(2) and the day of luteal transition, as calculated by one algorithm. The FSH peak was not closer to the day of follicular collapse than the peak values of urinary LH, serum FSH, or the day of luteal transition as calculated by a second algorithm. The most consistent correspondence between a hormone peak and ovulation was for serum E(2), serum FSH, serum LH, and urinary FSH. In 65 cycles for which urinary hormone data and ultrasound evaluations were available, the urinary FSH peak occurred within 1 day of follicular collapse in 97% of cycles. CONCLUSION(S) Urinary FSH is a useful biomarker for estimating the day of ovulation in population-based studies.

Live birth following in vitro maturation of oocytes retrieved from extracorporeal ovarian tissue aspiration and embryo cryopreservation for 5 years

OBJECTIVE To report a live birth after in vitro maturation (IVM) of oocytes retrieved from extracorporeal ovarian tissue aspiration in the setting of fertility preservation. DESIGN Observational study. SETTING Academic center. PATIENT(S) A 23-year-old woman. INTERVENTION(S) IVM from extracorporeal ovarian tissue aspiration. MAIN OUTCOME MEASURE(S) Live birth after IVM. RESULT(S) A 23-year-old woman conceived with embryos derived from extracorporeal oocyte aspiration followed by IVM, embryo freezing, and frozen embryo transfer. CONCLUSION(S) A healthy live birth from extracorporeal aspiration of immature oocytes, IVM, and a frozen embryo transfer after 5 years was documented. Consideration of this technique should be made as a primary or adjunct intervention in the setting of fertility preservation.

Ovulation after intravenous and intramuscular human chorionic gonadotropin

OBJECTIVE To define the time interval from intravenous and intramuscular hCG administration to follicular wall rupture and the endocrinologic events associated with ovulation. DESIGN Subjects were studied in two cycles and received hCG either 10,000 IU IM or 500 IU IV in a random sequence with an intervening spontaneous menstrual cycle. PATIENTS Thirty women from the University of Vermont Reproductive Endocrinology Service with unexplained, male, or cervical factor infertility. INTERVENTIONS Subjects underwent superovulation with clomiphene citrate followed by hCG administration when the lead follicle reached a mean diameter of 18 mm. Follicular rupture was determined by ultrasound monitoring every 2 hours starting 31 and 30 hours after intravenous and intramuscular hCG, respectively. Serum samples were obtained hourly for hormone measurements. The study was completed 2 hours after follicular rupture or 48 hours after hCG administration. RESULTS Twenty-five subjects received both intramuscular and intravenous hCG. The mean time to ovulation was 40.4 hours after intramuscular hCG (range, < or = 36 to > or = 48 hours) and 38.3 hours after intravenous hCG (range, 33 to > or = 48 hours). No differences were noted in the time interval to ovulation or rate of change in circulating E2 and P levels after IM versus IV hCG administration. CONCLUSIONS These findings suggest (1) ovulation occurs over a broad range of time after hCG administration; (2) ovulation does not occur in a more specific time interval after intravenous than intramuscular hCG; and (3) the rate of change in circulating E2 and P levels are not different after intravenous than intramuscular hCG.

Differences in hormonal characteristics of conceptive versus nonconceptive menstrual cycles

OBJECTIVE To determine the hormonal characteristics of a fecund menstrual cycle. DESIGN Prospective observational study. SETTING Clinical research center. PATIENT(S) Fourteen patients having artificial insemination with donor semen provided daily blood and urine samples in a nonconceptive cycle and the consecutive conceptive cycle. INTERVENTION(S) Concentrations of E2, luteinizing hormone, follicle-stimulating hormone (FSH), and P4 were measured in serum. Urine samples were analyzed for metabolites of E2, P4, and FSH. MAIN OUTCOME MEASURE(S) The serum and urinary hormone profiles of the periovulatory period were compared in conceptive and nonconceptive cycles. RESULT(S) The mean peak value of periovulatory urinary FSH was significantly higher in conceptive cycles than in nonconceptive cycles. The mean serum E2 concentration was significantly higher on day 0 (day of peak urinary FSH concentration) in conceptive cycles than in nonconceptive cycles, but mean peak values of serum E2 did not differ significantly. No other significant differences were observed in serum and urinary hormone profiles between conceptive and nonconceptive cycles. CONCLUSION(S) A lower, broader peak of FSH in urine was observed in nonconceptive cycles compared with conceptive cycles. Urinary FSH measurements may be useful in predicting less fecund ovulatory cycles and may identify some types of reduced female fertility.

A case of spontaneous ovarian hyperstimulation syndrome with a potential mutation in the hCG/LH receptor gene

The ovarian hyperstimulation syndrome (OHSS) is one of the most serious complications associated with ovulation induction. Most cases are associated with the use of exogenously administered gonadotropins and, occasionally, clomiphene citrate. Spontaneous OHSS in singleton gestations is extremely infrequent, and only a few cases have been described (1). We discuss a case of severe OHSS resulting from a singleton gestation conceived after spontaneous ovulation. We examined the patient’s hCG/LH receptor gene for a possible mutation to further explain her exaggerated response to normal circulating hCG levels from a singleton pregnancy.