Controlled ovarian hyperstimulation: a review for the non-ART patient.

Controlled ovarian hyperstimulation (COH) involves the administration of oral and/or injectable medications to induce ovulation in the anovulatory infertile patient, and superovulation in the ovulatory infertile patient. The different types of medication and protocols for COH are reviewed. Oral medications such as clomiphene and letrozole should be considered in most patients initially, except in the case of hypogonadotropic amenorrhea. Pregnancy rates are higher with the injectable medications, follicle stimualtion hormone (FSH) and human menopausal gonadotrpins (hMG), than oral medications; however, injectable medications have a higher risk of multiple gestation, ovarian hyperstimulation syndrome, cost and monitoring. Strategies to enhance the responsiveness to these medications in polycystic ovarian syndrome patients including adjunctive treatment with metformin and/or dexamethasone will be discussed. Combined protocols which use oral and injectable gonadotropins may also lower risks and costs without sacrificing chances of pregnancy. Patients with hypogonadotropic amenorrhea benefit from the addition of leutinizing hormone (LH) activity such as hMG, recombinant leutinizing hormone (rLH) or low dose human chroionic gonadotropin to FSH stimulation. Ovulation and luteal phase support with progesterone is generally recommended in injectable cycles but not with oral medications.

Ovarian morphology and serum hormone markers as predictors of ovarian follicle recruitment by gonadotropins for in vitro fertilization.

Twenty-five normal ovulatory women underwent three-dimensional transvaginal ultrasonography and blood sampling before and after oral glucose tolerance testing to compare ovarian morphology and circulating hormone levels in the early follicular phase as predictors of the number of oocytes retrieved after gonadotropin stimulation for in vitro fertilization. Serum levels of gonadotropins, inhibins, testosterone, dehydroepiandrosterone sulfate, and estradiol as well as summed ovarian volume were unrelated to oocyte number. Antral follicle number and serum androstenedione level, however, positively correlated, whereas postoral glucose tolerance test (post-OGTT) insulin release negatively correlated, with total and mature oocyte numbers. Adjusting for age and body mass index by regression analysis, the serum androstenedione level significantly predicted mature, but not total, oocyte number. The relationships of antral follicle number and post-OGTT insulin release to total oocyte number were additive; each was significant after controlling for the other. In contrast, antral follicle number significantly correlated with mature oocyte number after controlling for post-OGTT insulin release, whereas post-OGTT insulin release was unrelated to mature oocyte number after controlling for antral follicle number. Therefore, early follicular phase antral follicle number positively correlates with total and mature oocyte numbers after gonadotropin stimulation for in vitro fertilization and is linked to androgen and insulin actions in predicting ovarian follicle recruitment by gonadotropins.

Interstitial heterotopic pregnancy in a woman conceiving by in vitro fertilization after bilateral salpingectomy.

Heterotopic pregnancy, defined as the coexistence of an intrauterine pregnancy and an ectopic pregnancy, occurs in approximately 1 in 100 pregnancies conceived by in vitro fertilization (IVF), particularly when multiple embryos are transferred into the uterus. The ectopic gestation of the combined pregnancy usually occurs within the ampulla of the fallopian tube. If it implants within the interstitial portion of the fallopian tube, however, the resulting interstitial pregnancy eventually can rupture through the uterus, leading to sudden, severe hemorrhage and maternal death. This article describes the rupture of an interstitial heterotopic pregnancy in a 37-year-old woman conceiving by IVF after bilateral salpingectomy. The interstitial pregnancy was removed by laparotomy to protect the intrauterine pregnancy from damage. Physicians should consider interstitial ectopic pregnancy as a cause of abdominal pain, even when a viable pregnancy occurs by IVF after salpingectomy.

Current concepts in estrogen replacement therapy in the menopause.

OBJECTIVE: To provide a review of the risks and benefits of hormonal replacement therapy in the menopause, including new therapeutic regimens and modes of delivery. DESIGN: A review of the literature to identify published studies was accomplished using a computerized bibliographical search (Medline). RESULTS: Replacement therapy is effective in treating symptoms of estrogen deficiency and in lowering the risk of osteoporosis and cardiovascular disease. The daily administration of an estrogen and progestin eliminates the withdrawal bleed and increases patient compliance. This continuous form of therapy also consistently suppresses the endometrium, decreasing the risk of hyperplasia. More studies investigating the effect of continuous therapy on the lipid profile and cardiovascular disease are needed. CONCLUSIONS: New therapeutic regimens and modes of delivery decrease risk and increase patient acceptance of hormonal replacement therapy.

Characterization of D1Pas1, a mouse autosomal homologue of the human AZFa region DBY, as a nuclear protein in spermatogenic cells.

OBJECTIVE: To gain insight into the function of D1Pas1 in spermatogenesis. DESIGN: The cellular and subcellular distribution of D1Pas1 protein were examined. SETTING: Academic research laboratory. ANIMALS: Swiss Webster and C57B1/6J mice. INTERVENTION(S): Antibodies were generated against a D1Pas1 fusion protein. Immunoblot analysis was performed on lysates of testicular cells separated into enriched populations of spermatogenic cells and fractionated into nuclear and cytoplasmic compartments. Immunohistochemistry was performed on histological sections of testis from adult and postnatal day 17 mice. MAIN OUTCOME MEASURE(S): D1Pas1 protein distribution. RESULT(S): D1Pas1 was expressed in germ cells, and its expression was developmentally regulated because it was detected specifically in the meiotic and postmeiotic haploid stages of spermatogenesis. D1Pas1 protein was predominantly localized in the nucleus, with weak cytoplasmic staining. CONCLUSION(S): Nuclear localization of D1Pas1 in the testis and its sequence homology to putative RNA helicases suggests a role of D1Pas1 in pre-mRNA processing during spermatogenesis. Germ cell expression of D1Pas1 and homology to the Y chromosome gene DBY, which is located in an area deleted in azoospermia, suggests a potential role for an autosomal gene in the regulation of spermatogenesis.

Cyclin-dependent kinase 5 is expressed in both Sertoli cells and metaphase spermatocytes.

OBJECTIVE: To gain insight into the function of cyclin-dependent kinase 5 (Cdk5) in spermatogenesis. DESIGN: The expression of the Cdk5 protein was determined with the use of immunohistochemical and immunoblot analysis. SETTING: Academic research laboratory. ANIMAL(S): Adult mouse and archival human testicular tissue were used for the immunohistochemical analysis. Adult mice were used as the source of tissues for the immunoblot analysis. INTERVENTION(S): The immunohistochemical analysis was performed with an anti-Cdk5 antibody. The double immunohistochemical analysis was performed with anti-Cdk5 and alpha-tubulin antibodies. Immunoblotting was used to examine multiple mouse tissues for Cdk5 expression. MAIN OUTCOME MEASURE(S): Analysis of Cdk5 protein distribution. RESULT(S): Cdk5 was localized specifically within the cytoplasm of Sertoli cells and meiotic metaphase germ cells. The double immunohistochemistry analysis demonstrated the co-localization of Cdk5 and alpha-tubulin within the Sertoli cells. Western blot analysis revealed a high level of expression of Cdk5 in the testicular lysate. CONCLUSION(S): The cyclin-dependent kinases are known regulators of the cell cycle; however, Cdk5 expression previously has been described in terminally differentiated cells of the brain. The present evidence of an association between Cdk5 and microfilaments of Sertoli cells and meiotic metaphase germ cells suggests a role of Cdk5 in both seminiferous tubule function and meiosis.

Ultrasound-guided fallopian tube cannulation using Albunex.

OBJECTIVE: To test the role of transcervical fallopian tube catheterization under ultrasound (US) guidance using an ultrasound contrast agent. DESIGN: Catheterization was performed under US guidance in a patient with bilateral proximal tubal obstruction. SETTING: This study is a case report. PATIENT(S): Proximal tubal obstruction had been diagnosed on previous roentgenogram hysterosalpingography. INTERVENTION(S): Salpingography and tubal cannulation. MAIN OUTCOME MEASURE(S): Tubal patency was assessed using Albunex (Mallinckrodt Medical, St. Louis, MO) enhanced US. RESULT(S): Transvaginal catheterization was successful in achieving tubal patency. CONCLUSION(S): This catheterization technique should be investigated for possible use in the treatment of proximally obstructed tubes.

Embryo cryopreservation at the pronuclear stage and efficient embryo use optimizes the chance for a liveborn infant from a single oocyte retrieval.

OBJECTIVE: To estimate the potential for a liveborn in our program achieved through either fresh or frozen embryos derived from a single oocyte retrieval. DESIGN: Retrospective analysis. SETTING: A tertiary referral reproductive medicine unit. PATIENT(S): All consecutive patients undergoing oocyte retrieval from January 1, 1996, to June 30, 1997. INTERVENTION(S): All couples undergoing IVF-ET at our center are counseled about a specific embryo transfer number after oocyte retrieval based on demographic and historical factors. Only this specified number of embryos is retained in culture. All normally fertilized (2PN) oocytes exceeding this number are immediately cryopreserved at the pronuclear stage. For couples who do not conceive after fresh embryo transfers, frozen embryo transfers are subsequently performed by usually thawing only the number of embryos intended for transfer, thereby conserving remaining embryos for further potential frozen embryo cycles. MAIN OUTCOME MEASURE(S): Liveborn delivery per oocyte retrieval.39.0 years were 61.2%, 59.7%, and 18.5%, respectively. CONCLUSION(S): For women <39 years of age, the efficient use of embryo cryopreservation at the pronuclear stage and economical embryo utilization policies results in cumulative chances for a liveborn exceeding 60%.

Pronuclear stage cryopreservation after intracytoplasmic sperm injection and conventional IVF: implications for timing of the freeze.

OBJECTIVE: To compare clinical outcomes of frozen embryo transfers using cryopreserved pronuclear stage oocytes that had undergone either intracytoplasmic sperm injection (ICSI) or conventional IVF. DESIGN: Observational. SETTING: A tertiary referral reproductive medicine unit. PATIENT(S): Couples undergoing either ICSI or conventional IVF from January 1, 1995 to December 31, 1997. INTERVENTION(S): Patients underwent a standard controlled ovarian hyperstimulation protocol and transvaginal ultrasound-guided oocyte retrieval. All normally fertilized (2PN) oocytes exceeding a specified embryo number designated for fresh transfer were immediately cryopreserved at the pronuclear stage. Our cryopreservation method included timing of the freeze according to pronuclear morphology. Subsequent frozen embryo thaw-transfer cycles were usually performed by thawing only the intended number of embryos for transfer. MAIN OUTCOME MEASURE(S): Thaw survival rate, implantation rate, clinical pregnancy rate, delivery rate. RESULT(S): Ninety-six thaw-transfer cycles (n = 72) and 93 thaw-transfer cycles (n = 67) were undertaken in patients who had previously undergone conventional IVF or ICSI, respectively. Embryo thaw survival rates (IVF, 90.4%; ICSI, 91.1%) were similar. Clinical pregnancy (IVF, 40.6%; ICSI, 44.1%) and delivery (IVF, 36.4%; ICSI, 39.8%) rates per transfer, as well as implantation (IVF, 19.1%; ICSI, 19.9%) rates, were also similar. There were only four clinical pregnancy losses in both groups. CONCLUSION(S): Embryo thaw survival is similar for cryopreserved pronuclear stage oocytes derived from ICSI and conventional IVF. Clinical pregnancy, implantation and delivery rates were also similar for the two groups. In addition, there was no increase in the rate of pregnancy loss in ICSI patients after frozen embryo transfers.

Crinone 8% vaginal progesterone gel results in lower embryonic implantation efficiency after in vitro fertilization-embryo transfer.

OBJECTIVE: To evaluate the outcome of IVF-ET after the use of Crinone 8% (Wyeth-Ayerst Laboratories, Inc., Philadelphia, PA) vaginal progesterone gel and to compare these results with those seen in our program with the use of IM progesterone-in-oil. DESIGN: Retrospective cohort study. SETTING: A tertiary referral reproductive medicine unit. PATIENT(S): Patients <40 years of age undergoing IVF-ET cycles. INTERVENTION(S): Patients were treated with either Crinone 8% vaginal progesterone gel (90 mg) administered daily or IM progesterone-in-oil (50 mg) administered daily. MAIN OUTCOME MEASURE(S): Biochemical pregnancy rate, implantation rate, and clinical and ongoing pregnancy rates. RESULT(S): The use of Crinone 8% vaginal progesterone gel was associated with a lower implantation rate (16.6% versus 26.2%; odds ratio [OR] = 0.56; 95% confidence interval [CI], 0.35-0.89) compared with the use of IM progesterone-in-oil. Biochemical pregnancies were more common after the use of Crinone 8% vaginal progesterone gel as defined by either biochemical pregnancies per transfer (15.9% versus 5.7%; OR = 3.11; 95% CI, 1.17-8.32) or biochemical pregnancies as a proportion of positive serum hCG titers (29.2% versus 9.8%; OR = 3.80; 95% CI, 1.33-10.86). Clinical pregnancy rates also were lower with the use of Crinone 8% vaginal progesterone gel (36.4% versus 52.9%; OR = 0.51; 95% CI, 0.26-0.99). CONCLUSION(S): Implantation efficiency is reduced, as demonstrated by lower embryonic implantation rates and higher biochemical pregnancy rates, when Crinone 8% vaginal progesterone gel rather than IM progesterone-in-oil is used for luteal phase support after IVF-ET.

Anonymous oocyte donation performed exclusively with embryos cryopreserved at the pronuclear stage.

OBJECTIVE: To evaluate the clinical outcomes of patients who participated in an anonymous oocyte donation program that used embryos cryopreserved at the pronuclear stage. DESIGN: Observational study. SETTING: A tertiary care reproductive medicine unit. PATIENT(S): Anonymous oocyte donors and their respective recipients. INTERVENTION(S): Oocyte donors underwent a standard controlled ovarian hyperstimulation protocol and transvaginal ultrasound-guided oocyte retrieval. Oocyte recipients underwent at least one programmed hormone replacement cycle with transcervical ET. MAIN OUTCOME MEASURE(S): Thaw survival, implantation, clinical and ongoing pregnancy rates. RESULT(S): Thirty-six oocyte retrievals resulted in one ET to date. The mean numbers of oocytes that were retrieved and normally fertilized were 18.2 and 11.6, respectively. Fifty-one embryo thaw-transfer cycles were performed, with an embryo thaw survival rate of 93.5%. The clinical and ongoing pregnancy rates per ET were 52.9% and 51%, respectively. The overall implantation rate was 28.7%. The percentage of oocyte retrievals that resulted in at least one ongoing pregnancy to date was 69.4%. CONCLUSION(S): Anonymous oocyte donation can be conducted efficiently with the exclusive use of embryos cryopreserved at the pronuclear stage. This approach facilitates synchronization of the donor-recipient pair, eliminates the risk that recipients will begin hormonal therapy without embryo availability, and produces an acceptable ongoing pregnancy rate per oocyte donation.

Blood on the embryo transfer catheter is associated with decreased rates of embryo implantation and clinical pregnancy with the use of in vitro fertilization-embryo transfer.

OBJECTIVE: To examine the relation between blood found on the transfer catheter after ET and the rates of embryo implantation and clinical pregnancy with the use of IVF-ET. DESIGN: Retrospective cohort study. SETTING: A tertiary care center for assisted reproductive technology. PATIENT(S): Three hundred seven couples who underwent 354 ETs between January 1, 1994, and June 30, 1996. INTERVENTION(S): A semiquantitative system for recording the amount of blood found inside and outside the transfer catheter after ET. MAIN OUTCOME MEASURE(S): Embryo implantation rate and clinical pregnancy rate (PR). RESULT(S): Blood found outside the transfer catheter after ET was associated with decreased rates of embryo implantation and clinical pregnancy. In contrast, blood located inside the transfer catheter after ET, the type of catheter used for ET, the number of transfer attempts, and the time required for ET did not significantly affect either the embryo implantation rate or the clinical PR. CONCLUSION(S): Blood found outside, but not inside, the transfer catheter after ET is associated with lower rates of embryo implantation and clinical pregnancy with the use of IVF-ET. An emphasis on atraumatic transfer techniques, with prevention of bleeding at the time of ET, should contribute to improved pregnancy outcome with the use of IVF-ET.

Estrogens and Parkinson's disease.

There is substantial evidence that estrogens modulate the activity of dopamine in the extrapyramidal system. However, there is conflicting data as to the exact mechanism of estrogen's effects. The majority of clinical reports support an antidopaminergic effect of estrogens on Parkinsonian symptoms. Generally, Parkinsonism worsens with estrogen therapy. We report a case of improvement in Parkinsonian symptoms in a premenopausal patient when placed on leuprolide acetate. The pharmacologic menopause induced by leuprolide acetate leads to a hypoestrogenic state. We hypothesize that the decrease in estrogen improves Parkinson's disease symptoms via the relief of its antidopaminergic effects on the nigrostriatal pathway.

Hysteroscopic cervical cannulation under ultrasound guidance. A case report.

BACKGROUND: Ultrasound guidance has been recommended for various operative hysteroscopic procedures as an alternative to laparoscopic guidance. Ultrasound is noninvasive and may decrease the incidence of uterine perforation. CASE: A 30-year-old nulligravida presented for the evaluation of amenorrhea of two months' duration. She was diagnosed as having cervical obstruction and underwent operative hysteroscopy with cervical cannulation under ultrasound guidance. The patient's menstrual flow returned at the appropriate time without dysmenorrhea. CONCLUSION: Ultrasound guidance during hysteroscopy assisted in the proper orientation and position of the hysteroscope at the time of cannulation, potentially minimizing the risk of uterine perforation.

Recent advances in infertility treatment.

Infertility is defined as the inability to conceive after one year of regular coitus without contraception. Approximately 10% to 20% of childbearing-age couples are infertile in the United States. The demand for infertility investigations has increased dramatically in recent decades. The number of women using infertility services rose from 600,000 in 1968 to 1.35 million in 1988, an increase due, in part, to improved technology and increased publicity that began in the early 1980s. By 1995, the numbers were about 2.7 million. Recent advances in assisted reproductive technologies (ART) have provided greater possibilities for successful infertility treatment. Examples of new technologies include intracytoplasmic sperm injection, oocyte donation, and embryo cryopreservation.

Hysteroscopic cervical polypectomy with a polyp snare.

The cervical canal is difficult to visualize during hysteroscopy, making hysteroscopic maneuvers difficult. In our patient, after traditional surgical approaches failed, we used a polyp snare and closed the outflow channel of the hysteroscope, which allowed rapid removal of a cervical polyp in its entirety. This is an effective technique for excising intracervical lesions. (J Am Assoc Gynecol Laparosc 6(2):201-203, 1999)

A comparison of pain tolerance during X-ray hysterosalpingography and sonohysterosalpingography. Albunex Study Group.

The objective of this study was to determine patient perception of the level of discomfort during sonohysterosalpingography (sono-HSG) compared with standard X-ray hysterosalpingography (HSG). This was a prospective, operator-blinded, multicenter study using both numerical ranking and a visual analog scale to quantify discomfort. Sono-HSG utilizing Albunex was associated with a significantly lower mean intensity of pain than the instillation of X-ray contrast media. Sono-HSG is an alternative to X-ray HSG in the evaluation of the uterus and fallopian tubes and compares favorably with respect to patient discomfort.

Ovarian activity during follicular-phase down regulation in in vitro fertilization is associated with advanced maternal age and a high recurrence rate in subsequent cycles.

PURPOSE: Previous reports have suggested that the ovarian response to leuprolide acetate is predictive of in vitro fertilization pregnancy rates. This study evaluated the outcome of in vitro fertilization cycles complicated by elevated estradiol levels during leuprolide acetate down regulation and the outcome of subsequent cycles in the same patients. METHODS: Two hundred fifty-two in vitro fertilization cycles were initiated utilizing leuprolide acetate down regulation beginning on cycle day 1. RESULTS: Seventy-four of these cycles had an elevated estradiol level at the time of the baseline scan (28%). This group of patients had a higher maternal age, a higher cycle cancellation rate (27.5 vs 16.3%), and a high rate of recurrence on subsequent cycles (63%). CONCLUSIONS: The pregnancy rate per retrieval was equivalent in the two groups. This suggests that patients with advanced maternal age or a history of failure to suppress in a previous cycle may benefit from alternate regimens of superovulation.

Expression of cyclin E in gynecologic malignancies.

OBJECTIVE: This study investigated the patterns of expression of cyclin E in clear cell carcinoma and other gynecological cancers. METHODS: Immunohistochemistry was performed on paraffin-embedded archival specimens of ovarian, endometrial, cervical, and renal carcinomas. RESULTS: Expression of cyclin E was evident in epithelial ovarian carcinomas utilizing immunohistochemistry. Immunohistochemistry revealed a high level of expression of cyclin E in a subset of gynecologic carcinomas, namely clear cell carcinomas, but not in clear cell carcinomas of renal origin. CONCLUSION: These data suggest that an elevated level of immunohistochemical activity of cyclin E is a property of clear cell carcinomas of Müllerian origin. Immunohistochemistry with anti-cyclin E antibodies may serve as a useful method for diagnosing gynecologic clear cell carcinomas. Future studies are needed to confirm a possible increased activity of cyclin E in clear cell tumors.

Treatment of atypical endometrial hyperplasia with an insulin-sensitizing agent.

Endometrial cancer and hyperplasia have long been associated with diabetes. Hyperinsulinemia may have a direct mitogenic effect on the endometrium and may inhibit the effect of progestogen therapy. This case report describes the treatment of a patient with atypical endometrial hyperplasia with an insulin-sensitizing agent. A 37-year-old patient presented after failed treatment of endometrial hyperplasia with progestogen therapy. One month after initiating metformin therapy the patient's endometrial biopsy demonstrated proliferative endometrium. This patient's atypical endometrial hyperplasia regressed after the initiation of treatment with an insulin-sensitizing agent. This relatively new class of drugs may provide an adjunct to the therapy of endometrial hyperplasia.