Contribution of diminished ovarian reserve to hypofertility associated with endometriosis.

OBJECTIVE: To determine if ovarian reserve, as measured by day 3 levels of E2 and FSH, was different in patients with endometriosis as compared to controls. STUDY DESIGN: Case-control study of 75 women with laparoscopically staged endometriosis and 75 age-matched controls undergoing in vitro fertilization/embryo transfer for male factor infertility. RESULTS: In women with stage III/IV endometriosis (revised American Fertility Society staging), day 3 E2 and FSH levels were significantly higher than control levels (51.9 pg/mL and 12.6 mIU/mL versus 34.7 pg/mL and 9.7 mIU/mL, P < .03). In contrast, women with stage I/II endometriosis did not differ significantly when compared to controls (36.8 pg/mL and 10.4 mIU/mL versus 34.0 pg/mL and 10.2 mIU/mL). The total group showed significantly higher E2 levels (41.8 pg/mL versus 34.1 pg/mL, P < .03), but no significant differences in FSH levels were observed. CONCLUSION: These data show that women with stage III/IV endometriosis have relatively diminished ovarian reserve, while this situation is not noted in women with stage I/II endometriosis. This observation is consistent with progressive loss of ovarian reserve in women with increasing stages of endometriosis independent of age.

Fallopian sperm perfusion versus intrauterine insemination: a randomized controlled trial and metaanalysis of the literature.

OBJECTIVE: To determine whether fallopian sperm perfusion significantly improves pregnancy rates over intrauterine insemination (IUI) in infertile patients. DESIGN: Prospective, randomized, controlled trial and metaanalysis of the literature. SETTING: University-based infertility practice. PATIENT(S): Patients undergoing controlled ovarian stimulation were included in the prospective trial. They were <40 years of age and had no tubal obstructions, and their partners had no history of severe oligospermia. The metaanalysis was done using the patients with unexplained infertility from this study and from other randomized controlled trials found through a MEDLINE data base search. INTERVENTION(S): After undergoing controlled ovarian stimulation, the patients were randomly assigned to receive either IUI or fallopian sperm perfusion. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates. RESULT(S): Only the patients with unexplained infertility had a statistically higher pregnancy rate with fallopian sperm perfusion (odds ratio, 4.1; confidence interval, 1.1-16.4). A metaanalysis of the prospective randomized trials that provided data on patients with unexplained infertility showed a significant improvement in pregnancy rates with fallopian sperm perfusion (odds ratio, 1.9; confidence interval, 1.2-3). CONCLUSION(S): Fallopian sperm perfusion does not improve the chances of pregnancy in patients with infertility other than those with unexplained infertility. Fallopian sperm perfusion does significantly improve the pregnancy rates of patients with unexplained infertility who undergo controlled ovarian stimulation with gonadotropin/insemination protocols.

The need to step up the gonadotropin dosage in the stimulation phase of IVF treatment predicts a poor outcome.

PURPOSE: It is a common practice to increase the gonadotropin dose during ovarian stimulation when the estradiol (E2) rise is found to be inadequate. The prognostic impact of the use of this step-up regimen on the outcome of the affected in vitro fertilization (IVF) cycle is the subject of this study. METHODS: This is a retrospective analysis of IVF cycles in a series of consecutive patients who required an increase in the gonadotropin dosage during the stimulation phase because of inadequate E2 rise. Controls consisted of patients in whom the dose was not increased. After 4 days of stimulation, the gonadotropin dosage was increased if E2 levels failed to rise by 70% every 2 days. Outcome was defined in terms of maximum E2 level, number of follicles at aspiration, number of oocytes obtained, fertility rate, and pregnancy rate and was compared in study and control patients. Pregnancy was defined by sonographic demonstration of cardiovascular activity. RESULTS: One hundred forty-five patients were analyzed. A step-up regimen was used in 35 patients (24.1%). Patients who required the step-up dosing had significantly lower peak E2 levels (1373 vs 1828 pg/ml; P < 0.005), fewer follicles measuring greater than 16 mm (7.2 vs 9.7; P < 0.003), and fewer oocytes recovered (8.3 vs 11.2; P < 0.009). The fertilization rate (67.6 vs 64.2%) was not significantly different. The pregnancy rate (8.5 vs 32.7%; P < 0.004) was significantly lower in the group requiring the step-up regimen. CONCLUSIONS: The utilization of a step-up regimen during an IVF treatment cycle is a predictor of a poor outcome for the specific IVF cycle. As this information is available before retrieval, consideration of cycle cancellation may be appropriate.

Good luck rites in contemporary infertility.

OBJECTIVE: To explore whether contemporary women use good luck rites in the infertility situation. STUDY DESIGN: Prospective study in a tertiary infertility center where women were asked to describe any type of good luck act performed on the day of critical medical intervention (either intrauterine insemination or embryo transfer) to achieve pregnancy. RESULTS: Four hundred thirty-eight consecutive infertile women participated. Good luck rituals, as defined by patients, included prayer, wearing of objects, fantasies and other acts performed specifically on the day of the medical intervention. While 40% of the study population reported engaging in a good luck act prior to intrauterine insemination of embryo transfer, there was no significant difference in pregnancy rates observed in women reporting utilization versus nonutilization of fertility rituals. CONCLUSION: This study indicated that good luck rites are commonly performed by women undergoing infertility procedures on the day of a critical intervention. The fact of their common presence attests to their importance for the well-being of the individual; however, there is no evidence of direct benefit in terms of higher pregnancy rates. The possibility of secondary benefits needs to be explored further.

Conscious sedation for in vitro fertilization.

OBJECTIVE: To review the principles and practice of the use of conscious sedation for IVF. DESIGN: The pertinent literature was reviewed and recommendations are provided. RESULT(S): Conscious sedation appears to be the most commonly used method of pain relief for transvaginal retrieval of oocytes. Conscious sedation does not require the presence of an anesthesiologist and can be done in freestanding clinics. Agents commonly used include opioids in combination with benzodiazepines. This combination minimizes pain, decreases anxiety, and provides sedation and some amnesia. Adjuvants such as promethazine and hydroxyzine can also be used but often are not needed. Conscious sedation is well tolerated by patients and does not require highly specialized equipment. However, there are specific safeguards that should be followed. Only a few toxicity studies have been performed, but they are reassuring because they have not found significant effects on fertilization or cleavage. CONCLUSION(S): Conscious sedation appears to be a safe and cost-effective method of providing analgesia and anesthesia for transvaginal retrieval of oocytes.

Leukocytosis in response to exogenous gonadotrophin stimulation.

Leukocytosis may develop in women undergoing ovulation induction. The production of blood leukocytes and their numbers in circulation are regulated by complex interactions involving endogenous haematopoietic cytokines, such as granulocyte-colony stimulating factor (G-CSF), monocyte-colony stimulating factor (M-CSF), and interleukins. The purpose of this prospective study was to explore the presence of leukocytosis in women who receive urinary menotrophins, and to determine whether haematopoietic cytokines are changed in the stimulation process. Controls were volunteers of the same age range, not taking any medication, who received daily saline injections. Subjects underwent phlebotomy at defined points for determination of complete blood counts, G-CSF, M-CSF, and interleukin-6 concentrations. Baseline white blood cell (WBC) counts were similar in patients and controls. In menotrophin-treated patients the WBC counts rose significantly (4.19 +/- 0.28 to 6.37 +/- 0.71) during the stimulation and peaked in the luteal phase (P = 0.037). In contrast, WBC counts decreased in controls. Other leukocytic lineages were not affected. In treated patients G-CSF concentrations rose significantly (P = 0.028 versus controls), while changes in M-CSF and interleukin-6 were not significant.

Detrimental effect of hydrosalpinx fluid on the development and blastulation of mouse embryos in vitro.

OBJECTIVE: To study the effects of human hydrosalpinx fluid on mouse embryo blastulation rate. DESIGN: Comparison of mouse embryo blastulation rate in media containing increasing concentrations of hydrosalpinx fluid. SETTING: Tertiary care center. PATIENT(S): Women undergoing laparoscopic evaluation or treatment for infertility noted to have hydrosalpinx or paratubal cyst. INTERVENTION(S): Exposure of mouse embryos to hydrosalpinx or paratubal cyst fluid collected during laparoscopy. MAIN OUTCOME MEASURE(S): Blastulation rate of mouse embryos. RESULT(S): Culture of mouse embryos at 0% (controls), 0.3%, 0.6%, and 0.9% hydrosalpinx fluid concentrations demonstrated significantly lower blastulation rate at each level compared with the controls. CONCLUSION(S): Hydrosalpinx fluid is highly embryotoxic.

Sonographic assessment of endometrial pattern and thickness in patients treated with clomiphene citrate, human menopausal gonadotropins, and intrauterine insemination.

OBJECTIVE: To analyze the endometrium sonographically in patients undergoing controlled ovarian stimulation with clomiphene citrate (CC) in addition to menotropins to determine the significance of endometrial pattern and thickness on pregnancy rate (PR). DESIGN: A prospective study analyzing patients receiving sequential CC and hMG followed by hCG and IUI. Patients who exhibited homogeneous endometrial patterns were compared with those who had trilaminar patterns visualized by transvaginal sonography at the end of the follicular phase. Endometrial thickness was emphasized in this group of patients. SETTING: Tertiary infertility center. PATIENT(S): All patients receiving sequential CC and hMG therapy at a tertiary infertility center. INTERVENTION(S): All patients received individualized dosing of hMG after 5 days of CC. Transvaginal sonography was performed 15 hours before hCG administration. Intrauterine insemination was performed 36 hours after hCG injection. MAIN OUTCOME MEASURE(S): Occurrence of pregnancy as determined by serially rising beta-hCG titers and sonographic confirmation. RESULT(S): During the study period, 223 patients were analyzed. Fifty patients had a homogeneous endometrium, whereas 173 patients had a trilaminar pattern. In the homogeneous group, the PR was 8%, and in the trilaminar group it was 21%. There was no significant difference in age, parity, diagnosis, peak E2 level, and mature follicle number between the two groups. Although homogeneous patterns were associated with thinner endometrium, no difference in PRs could be discerned within the trilaminar group on the basis of endometrial thickness. CONCLUSION(S): In patients receiving sequential CC and hMG ovarian stimulation, a homogeneous endometrial pattern on the day of hCG administration predicts a significantly decreased PR compared with a trilaminar pattern.

The predictive value of first-trimester embryonic heart rates in infertility patients.

OBJECTIVE: To analyze whether first-trimester embryonic (fetal) heart rates (FHR) are useful in predicting pregnancy outcome for infertility patients. METHODS: Patients in a university-based reproductive endocrinology and infertility practice were studied prospectively. Infertile women who achieved clinical pregnancy underwent first-trimester transvaginal sonographic evaluation, and FHR in patients achieving viable pregnancies were compared with those experiencing fetal loss. RESULTS: Overall, 99 pregnancies reached viability and 17 resulted in fetal loss before 20 weeks' gestation. Patient age, methods of conception, and number of previous fetal losses did not differ significantly between the two groups. A significant correlation (r = .70, P < .001) was found between increasing FHR levels and advancing gestational age in patients with viable pregnancies and, although to a weaker extent, patients who miscarried (r= .52, P < .05). A significantly higher number of viable pregnancies, compared with fetal losses, had FHR falling within one (70.7% compared with 41.2%, P < .025) and two (99.0% compared with 64.7%, P < .001) standard deviations of the mean for viable pregnancies at corresponding gestational ages. The majority of FHR of failing pregnancies fell below the individual reference ranges. CONCLUSION: First-trimester FHR can help predict pregnancy outcome for infertility patients. Women with FHR outside the reference range from the mean for viable pregnancies at corresponding gestational ages may be at risk for eventual pregnancy loss.

An eight year review of hospitalization for ovarian hyperstimulation syndrome.

We analyzed the etiologic factors and trends of hospitalization for ovarian hospitalization syndrome (OHSS) resulting from the use of fertility medications. From May, 1986 through April, 1994, patients hospitalized with OHSS were exclusively admitted to the University Hospital. Analysis was performed with regards to treatment method, severity of hyperstimulation, and onset of disease. Overall, 14 patients were hospitalized for a rate per cycle of 0.1% (14/14, 283). The rate of admission for patients undergoing superovulation (9/12, 945; .07%) was significantly lower than for those undergoing assisted reproductive techniques (ART) (5/1, 338; .37%). The total number of injectable gonadotropin ampules used was also higher in patients admitted following ART versus superovulation. A significantly greater number of patients presenting with late developing hyperstimulation syndrome (5/7; 71.4%) manifested severe disease as opposed to those hospitalized with early onset OHSS (1/7; 14.3%). Our data suggest that hospital admission is an infrequent event following the use of fertility medications, and patients are more likely to be hospitalized with OHSS following ART than superovulation.

Direct gamete uterine transfer in patients with tubal absence or occlusion.

PURPOSE: Our aim was to examine the potential of the uterine cavity to affect fertilization and early embryo development. DESIGN: A prospective IRB-approved protocol for patients fulfilling study eligibility criteria was used. METHODS: Patients studied included those with primary or secondary infertility, aged less than 38 years, with no history of severe male-factor infertility, and with hysterosalpingogram- and laparoscopic-confirmed bilateral proximal tubal occlusion. Superovulation induction was accomplished with a combination of GnRH agonist and menotropins, with serum hormonal and sonographic monitoring. Within 24 hr prior to, and again at the time of, ovulatory hCG administration, progesterone (P4) was given. Sonographic-guided transvaginal retrieval was performed 35 hr after hCG. Between four and six oocytes were returned to the uterine cavity, admixed with sperm, immediately following retrieval. Luteal support consisted of daily P4 administration. RESULTS: Of the 20 patients recruited for the study, all completed the retrieval and transfer procedure. A total of four clinical pregnancies was achieved, with one early first-trimester loss, one late first-trimester loss (Trisomy 14), and two healthy term infants delivered. IVF of surplus oocytes demonstrated a 82.5% fertilization rate and 66.7% cleavage following cryopreservation. CONCLUSIONS: Human fertilization can be achieved through direct uterine transfer of gametes. Furthermore, administration of P4 prior to the ovulatory dose of hCG is compatible with in vitro or in vivo fertilization and implantation.

Is the endometrial suction curette useful in the detection of chorionic villi during the first trimester?

OBJECTIVE: Early diagnosis of ectopic pregnancy is important for its medical management. Algorithms used for the diagnosis of ectopic pregnancy recommend obtaining a tissue diagnosis to rule out an intrauterine pregnancy when it is clear that a pregnancy is abnormal, but a stage of sonographic visualization has not been attained. The ability of an endometrial suction curette to identify products of conception early in pregnancy has not been documented. The purpose of this study was to determine the efficacy of an endometrial suction curette in detecting products of conception during the first trimester. METHODS: Twenty patients scheduled for termination of pregnancy via D&C agreed to endometrial sampling prior to dilatation of the cervix. All patients had transvaginal sonography which verified the gestational age. The specimen was evaluated microscopically after staining. RESULTS: Chorionic villi were identified in 14 of 20 (70 per cent) specimens as seen with light microscopy. CONCLUSION: An endometrial suction curette identifies chorionic villi from an intrauterine gestation in the first trimester with a sensitivity of 70 per cent. While most patients with an intrauterine gestation can be identified using an endometrial suction curette to obtain trophoblastic tissue, the absence of this tissue does not definitively identify an ectopic pregnancy. Therefore, the routine use of the endometrial biopsy in the algorithms for the diagnosis and treatment of ectopic pregnancy should be approached with caution.

Vulvar edema as a complication of laparoscopic surgery.

Vulvar edema occurred in three women within 24 hours after operative laparoscopy. In addition to local swelling and discomfort, inability to void was a common complaint. All three patients were treated with Foley catheter urinary drainage, local application of ice packs, and bedrest for 1 to 2 days with spontaneous resolution of the edema. We conclude that vulvar edema is a possible complication of endoscopy. Although it may require hospitalization because of inability to void, the condition is self-limited.

Sonographic assessment of endometrial pattern and thickness in patients treated with human menopausal gonadotropins.

OBJECTIVE: To analyze sonographically the endometrium in patients undergoing controlled ovarian stimulation with menotropins in order to determine the significance of endometrial pattern and thickness on pregnancy rate. DESIGN: This is a prospective, nonrandomized study comparing pregnancy rates in patients with hyperechoic homogeneous patterns with those in patients with isoechoic or hypoechoic trilaminar patterns. SETTING: Tertiary infertility center. PATIENTS: All patients receiving menotropin therapy at a tertiary infertility center. INTERVENTIONS: All patients received individualized dosing of hMG starting on cycle day 3. Transvaginal sonography was performed 15 hours before hCG administration and the endometrium was assessed. MAIN OUTCOME MEASURE: Occurrence of pregnancy as determined by serially rising beta-hCG titers and sonographic confirmation. RESULTS: During the study period, 175 patients were evaluated. Thirty-four (19%) patients had a homogeneous endometrium, whereas 141 (81%) patients had a trilaminar pattern. There was 1 pregnancy (2.9%) among women with a homogeneous endometrial pattern and 33 pregnancies (23%) among those with a trilaminar pattern. No significant differences were found in mean E2 level, follicle numbers, parity, and diagnosis between the two groups. CONCLUSION: In patients receiving menotropins, a homogeneous pattern is a bad prognostic sign, regardless of endometrial thickness.

Recurrent cervical pregnancy after assisted reproduction by intrafallopian transfer.

BACKGROUND: Cervical pregnancy is an uncommon, yet potentially catastrophic form of ectopic pregnancy. Early diagnosis and intervention are important in avoiding short-term and long-term morbidity. Although transcervical embryo transfer is thought to increase the incidence of this phenomenon in patients undergoing in vitro fertilization, its occurrence after intrafallopian transfer is rarely seen. CASE: A 43-year-old nulliparous white female with a history of unexplained infertility experienced recurrent cervical pregnancy after two consecutive gamete/zygote intrafallopian transfer cycles. Abnormally rising beta-hCG levels combined with transvaginal sonography helped establish the diagnosis in each case. Intramuscular (IM) methotrexate combined with intra-amniotic potassium chloride successfully treated this condition initially, and IM methotrexate alone was sufficient for successful treatment in the second case. CONCLUSION: Cervical pregnancy may occur with assisted reproductive techniques involving intrafallopian transfer. Early diagnosis may be important for successful treatment of cervical pregnancy with conservative measures. Even in the case of recurrence, prompt intervention may allow for preservation of a patient's future fertility potential.

Does the absence or presence of seminal fluid matter in patients undergoing ovulation induction with intrauterine insemination?

Sperm preparations for intrauterine insemination (IUI) generally do not include seminal fluid, and it is not known whether the absence of this component affects pregnancy rates. Therefore we evaluated the effect of high intravaginal seminal fluid deposition on clinical pregnancy rates in patients undergoing ovulation induction and IUI therapy. A prospective, randomized, double-blind study was designed for an infertile population in a university-based infertility practice. Patients were randomized to receive high vaginal deposition of either seminal fluid separated from the husband's ejaculate (study group) or normal saline solution (control group). Intercourse was restricted. A comparison of clinical pregnancy rates per cycle between study and control groups showed no significant difference between them [22/164 (13.4%) and 19/155 (12.3%) respectively]. Furthermore, in non-participants with unregulated intercourse, the pregnancy rate per cycle was not significantly different (40/307; 13.0%). Miscarriage rates between the study and control groups were similar. As high intravaginal deposition of seminal fluid at the time of IUI does not improve the clinical pregnancy rate in patients undergoing ovulation induction and IUI therapy, our study suggests that, after ejaculation, clinically significant biological contributions of seminal fluid to the achievement of pregnancy are bypassed by well-timed IUI.

Ovulation induction combined with intrauterine insemination in women 40 years of age and older: is it worthwhile?

The use of ovulation induction combined with intrauterine insemination (IUI) as a treatment for subfertility in women with patent Fallopian tubes has increased in recent years. Little is known regarding the efficacy of this treatment in women aged >/=40 years. We reviewed our data in our ovulation induction with IUI programme for 168 consecutive patients aged >/=40 years undergoing a total of 469 cycles of treatment. Either sequential clomiphene citrate and human menopausal gonadotrophins or daily gonadotrophins were utilized along with timed IUI insemination. In 402 completed cycles, 28 clinical pregnancies occurred. The pregnancy loss rate was 34.4%. The overall ongoing/viable pregnancy rates per initiated and completed cycles were 4.47 and 5.22% respectively. No viable pregnancies occurred in 136 cycles in women aged >/=43 years. The ongoing/variable cycle fecundity rates for women aged 40, 41, and 42 years were 9.6, 5.2, and 2.4% per cycle respectively. When utilized in women aged >=40 years, ovulation induction with IUI is most likely to result in successful pregnancy in women 40-42 years of age. Women >/=43 years should consider other alternatives such as adoption or egg donation.

Evaluation of serum creatine kinase levels in ectopic pregnancy.

OBJECTIVE: To analyze whether increased serum creatine kinase (CK) levels are useful in early detection of ectopic pregnancy (EP). DESIGN: Prospective cohort study. SETTING: Patients in a university-based reproductive endocrinology and infertility practice. PATIENTS: Infertile women who achieved clinical pregnancy. INTERVENTIONS: Serum CK with isoenzymes levels were drawn after sonographic evaluation in patients achieving clinical pregnancy. MAIN OUTCOME MEASURES: Comparison of serum CK levels in patients with EP versus those with normal and abnormal intrauterine pregnancy (IUP), both separately and together as one group. RESULTS: There was no significant difference in mean total CK levels for patients with EP (82.25 +/- 81.39 IU/L; conversion factor to SI unit, 1.00) versus normal IUP (62.54 +/- 44.79 IU/L), abnormal IUP (55.15 +/- 3.46 IU/L), or all IUP (60.87 +/- 40.72 IU/L). The mean gestational ages were similar in all three groups: EP, 46.78 +/- 6.65 days; normal IUP, 47.56 +/- 8.29 days; and abnormal IUP, 47.86 +/- 13.30 days. CONCLUSION: Serum CK levels do not help to predict EP for infertility patients achieving conception. To assist in preventing maternal morbidity, a more discriminative test is needed to identify this condition early in gestation.

Reversible alopecia after single-dose methotrexate treatment in a patient with ectopic pregnancy.

OBJECTIVE: To report a case of a women who received a single 50 mg/m2 dose of methotrexate (MTX) on two occasions for two separate ectopic pregnancies. After both treatments the patient experienced reversible alopecia. DESIGN: Case report. SETTING: Single human patient in a university-run clinic. PATIENTS: A patient with an ectopic pregnancy presenting for treatment on two separate occasions. INTERVENTIONS: A single dose of 50 mg/m2 MTX given to the patient on both occasions. MAIN OUTCOME MEASURE: Loss of scalp hair. RESULTS: On two separate occasions the patient lost a significant portion (33% to 50%) of her scalp hair. CONCLUSION: Even single-dose MTX as used for the treatment of ectopic pregnancy may induce alopecia in a susceptible patient.