Eric S. Surrey

Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques

OBJECTIVE To assess the efficacy of various controlled ovarian hyperstimulation (COH) regimens in the prior poor-responder patient preparing for assisted reproductive techniques. DESIGN English-language literature review. PATIENT(S) Candidates for assisted reproductive techniques who had been defined as having a prior suboptimal response to standard COH regimens. INTERVENTION(S) A variety of regimes are reviewed, including increased gonadotropin doses, change of gonadotropins, adjunctive growth hormone (GH), luteal phase (long) GnRH agonist (GnRH-a) initiation, early follicular phase (flare) GnRH-a initiation, low-dose luteal phase (ultrashort) GnRH-a initiation, progestin pretreatment, and microdose flare GnRH-a initiation. MAIN OUTCOME MEASURE(S) Maximal serum E(2) levels, follicular development, dose, and duration of gonadotropin therapy, cycle cancellation rates, oocytes retrieved, embryos transferred, and clinical and ongoing pregnancy rates. RESULT(S) A lack of uniformity in definition of the poor responder and of prospective randomized trials make data interpretation somewhat difficult. Of the varied strategies proposed, those that seem to be more uniformly beneficial are microdose GnRH-a flare and late luteal phase initiation of a short course of low-dose GnRH-a discontinued before COH. CONCLUSION(S) No single regimen will benefit all poor responders. General acceptance of uniform definitions and performance of large-scale prospective randomized trials are critical. Development of a reliable precycle screen will allow effective differentiation among normal responders, poor responders, and those who will not conceive with their own oocytes.

Clinical and Endocrine Effects of a Microdose GnRH Agonist Flare Regimen Administered to Poor Responders Who Are Undergoing In Vitro Fertilization

OBJECTIVE To assess the endocrine and clinical responses to microdose GnRH agonist (GnRH-a) that was administered in the early follicular phase before controlled ovarian hyperstimulation to poor responders who were candidates for IVF-ET. DESIGN Prospective nonrandomized trial with historical controls. SETTING Tertiary care university-affiliated infertility practice. PATIENT(S) Thirty-four IVF-ET candidates with a prior poor response to a standard long-protocol GnRH-a controlled ovarian hyperstimulation regimen (cycle A). Patients were divided into two groups based on their age at the initiation of cycle A (Group 1: < or = 39 years, n = 15; Group 2: > or = 40 years, n = 19). INTERVENTION(S) Low-dose oral contraceptive (x 21 d) followed by GnRH-a (leuprolide acetate; 40 micrograms s.c. b.i.d.) flare and urofollitropin initiated on day 3 of GnRH-a administration (cycle B). MAIN OUTCOME MEASURE(S) Comparative analysis of clinical responses (total urofollitropin dose used and number of oocytes retrieved as well as fertilization and clinical and ongoing pregnancy rates) and endocrine responses (serum E2, FSH, LH, T, and P levels) between cycles A and B in the two groups. Early follicular phase serum E2 and FSH changes in groups 1 and 2 were compared with changes in nine normal responder controls who were receiving a standard long-protocol GnRH-a/urofollitropin regimen (group 3). RESULT(S) Maximal E2 levels as well as clinical and ongoing pregnancy rates were higher in cycle B patients receiving microdose GnRH-a. Cancellation rates in cycle B were lower than in cycle A. Statistically significant increases in treatment day 6 serum FSH levels were noted during cycle B in both groups 1 and 2 but not in group 3 controls. No abnormal rises in LH, P, or T were noted in any of the groups. CONCLUSION(S) Microdose GnRH-a enhances urofollitropin response and clinical outcome in poor responders undergoing IVF-ET. This may be due to enhanced release of early follicular phase endogenous FSH without concomitant deleterious rises in androgen levels or corpus luteum rescue.

Impact of intramural leiomyomata in patients with a normal endometrial cavity on in vitro fertilization–embryo transfer cycle outcome

OBJECTIVE Assess the impact of intramural uterine leiomyomata and a normal endometrial cavity on IVF-ET cycle outcome. DESIGN Retrospective case-controlled analysis. SETTING Tertiary-care-assisted reproductive technology program. PATIENT(S) Three hundred ninety-nine consecutive fresh IVF-ET cycles were performed in patients with a normal precycle diagnostic hysteroscopy; patients were divided into four groups. Group 1: positive leiomyomata, age <40 years (n = 51 cycles); group 2: negative leiomyomata, age <40 years (n = 57 cycles); group 3: positive leiomyomata, age > or =40 years (n = 22 cycles); group 4: negative leiomyomata, age > or =40 years (n = 59 cycles). A subgroup of all group 2 patients aged 35-39 (group 2A, n = 113 cycles) was also evaluated as an additional control. INTERVENTION(S) Controlled ovarian hyperstimulation, IVF-ET. MAIN OUTCOME MEASURE(S) Implantation (IR), live birth (LBR) rates. RESULT(S) There were no significant differences in LBR among age-matched controls: group 1 (49%) versus 2 (57.5%) or 2A (57%) and group 3 (40.9%) versus 4 (32.2%). IR was significantly lower in group 1 (21.4%) versus 2 (33.3%) or 2A (33.9%) but not in group 3 (17.5%) versus 4 (11.6%). Implantation did not correlate with either mean leiomyoma diameter or volume. CONCLUSION(S) [1] LBR was not affected by the presence of intramural leiomyoma in IVF-ET patients with hysteroscopically normal endometrial cavities. [2] A significant decrease in IR was only noted in patients <40 years old. [3] Given the relatively high LBR in all groups, prophylactic surgical intervention cannot be justified, but precycle hysteroscopy evaluation is recommended.

Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization- embryo transfer in patients with endometriosis

OBJECTIVE To evaluate the effect of a 3-month course of GnRH agonist administered immediately before IVF-ET in infertile patients with endometriosis. DESIGN Prospective, randomized trial. SETTING Three tertiary care assisted reproductive technology programs. PATIENT(S) IVF-ET candidates with surgically confirmed endometriosis. INTERVENTION(S) Twenty-five patients received three courses of a long-acting GnRH agonist, 3.75 mg i.m. every 28 days, followed by standard controlled ovarian hyperstimulation. Twenty-six patients received standard controlled ovarian hyperstimulation with mid-luteal phase GnRH agonist down-regulation or microdose flare regimens. MAIN OUTCOME MEASURE(S) Response to controlled ovarian hyperstimulation, ongoing pregnancy rates per cycle, group implantation rates, and implantation rate per embryo transfer procedure. RESULT(S) The extent of surgically confirmed endometriosis was greater in patients who received the long-acting GnRH regimen for 3 months before IVF-ET. The groups did not differ significantly in terms of dose or duration of gonadotropin stimulation, number of oocytes retrieved, fertilization rate, or number of embryos transferred. Patients who received the long-acting GnRH regimen had significantly higher ongoing pregnancy rates (80% vs. 53.85%) and a trend toward higher implantation rates (42.68% vs. 30.38%). CONCLUSION(S) Prolonged use of GnRH agonist before IVF-ET in patients with endometriosis resulted in significantly higher ongoing pregnancy rates than did standard controlled ovarian hyperstimulation regimens. No deleterious effect on ovarian response was observed.

Effect of peritoneal fluid from endometriosis patients on endometrial stromal cell proliferation in vitro.

Late proliferative phase endometrial stromal cells grown in short-term culture were used as a model for the stromal component of endometriotic implants. Cells were grown in medium alone and in medium supplemented by 5, 10, and 20% concentrations of the cell-free fractions of peritoneal fluid obtained from patients with and without endometriosis. Nine fluid-sample pairs were matched based on the presence or absence of endometriosis at laparoscopy and the similarity of peritoneal fluid estradiol concentrations. Stromal cell proliferation as reflected by 3H-thymidine incorporation during sequential cell harvests over 72 hours was greater for cells exposed to endometriosis peritoneal fluid than for those exposed to non-endometriosis peritoneal fluid. This reached statistical significance with exposure to peritoneal fluid concentrations of 10 and 20% (P less than .05). A linear dose-response relationship between 3H-thymidine incorporation and peritoneal fluid concentration could be derived only for stromal cells exposed to fluid samples obtained from endometriosis patients (r = 0.51; P less than .001). In addition, proliferation over 72 hours was significantly greater for cells grown in 20% endometriosis peritoneal fluid than for those grown in nutrient medium alone (P less than .001). These data imply that factor(s) secreted into the peritoneal fluid of endometriosis patients may play a role in the proliferation or maintenance of disease implants.

A prospective randomized comparison of luteal phase versus concurrent follicular phase initiation of gonadotropin-releasing hormone agonist for in vitro fertilization *

OBJECTIVE To compare the effects of gonadotropin-releasing hormone agonist (GnRH-a) initiation either preceding or concurrent with controlled ovarian hyperstimulation (COH) in patients undergoing in vitro fertilization-embryo transfer (IVF-ET). DESIGN Fifty-five patients were prospectively randomized to receive either GnRH-a on cycle day 21 before COH until ovarian suppression was achieved (group I) or GnRH-a concurrently with COH commencing on cycle day 3 (group II). MAIN OUTCOME MEASURES Serum gonadotropin and ovarian steroid hormone levels, as well as fertilization, spontaneous abortion, and live birth rates. RESULTS Twenty-six patients in group I and 29 patients in group II underwent COH for IVF-ET. Patients in group II had significantly higher serum luteinizing hormone, progesterone, and testosterone levels during stimulation with human menopausal gonadotropins (hMG) before oocyte retrieval (P < 0.05). Despite similar fertilization, biochemical, and clinical pregnancy rates, the spontaneous abortion rate was higher in group II (5/6) compared with group I (1/7) (P < 0.05). Thus, the live birth rate/retrieval for group I was 6 of 24 (25%) as compared with that of group II, which was 1 of 26 (3.8%) (P < 0.05). CONCLUSIONS The initiation of GnRH-a in the follicular phase concurrently with hMG is associated with evidence of premature luteinization, hyperandrogenemia, and poorer pregnancy outcome compared with luteal phase administration of GnRH-a before hMG for IVF-ET.

Falloposcopic classification and treatment of fallopian tube lumen disease

OBJECTIVE To devise a diagnostic classification and scoring system for tubal lumen disease based on falloposcopy and to evaluate it against tuboplasty procedures and pregnancy outcomes. DESIGN Prospective study approved by the hospital Institutional Review Board. SETTING Academic tertiary infertility center. PATIENTS Seventy-five women with hysterosalpingographic and laparoscopic evidence of endotubal disease had 112 tubes available for falloposcopic evaluation. INTERVENTION Diagnostic and operative falloposcopy was performed, when indicated, using aquadissection, flexible wire cannulation, or direct balloon tuboplasty. RESULTS The endotubal lumens were considered to be falloposcopically normal in 52 tubes (46%), to contain mild to moderate disease in 33 (29%), and severe to obstructive disease in 27 (25%) cases. Within a year of the procedure, 6 of the 28 women (21%) in whom at least 1 tube was normal conceived, in 2 of 22 (9%) with mild to moderate disease, and in 0 of 16 (0%) with severe endotubal disease. CONCLUSIONS Falloposcopy provides a visual means of scoring endotubal disease and may be intrinsically therapeutic for dislodging intraluminal debris and breaking down filmy adhesions in normal or minimally diseased tubes. The presence of severe disease remains resistant to the use of current endotuboplasty treatments as reflected by poor pregnancy outcome, and such women should be provided the option of microsurgical tubal repair or in vitro fertilization and embryo transfer procedures.

Falloposcopy: a microendoscopic technique for visual exploration of the human fallopian tube from the uterotubal ostium to the fimbria using a transvaginal approach * †

A transvaginal microendoscopic technique has been developed for safely exploring the human fallopian tube from the utero tubal ostium to the fimbria and adjacent peritoneal cavity. Falloposcopy was performed without complication or evidence of endotubal damage in 44 women, 38 of whom also underwent a concurrent laparoscopy. Eight women with normal tubes served as controls and 36 women with tubal damage underwent falloposcopy in an attempt to document endotubal defects. Previous salpingectomy in 13 women and ostial obstruction in 4 cases left 71 tubes available for falloposcopy. Technical failures, defined as an inability to negotiate the tubal lumen in the absence of obstructive disease occurred in 8 of 71 (11%) procedures. In 63 successful procedures, the tubal lumen was considered to be falloposcopically normal in 28 cases (44%) and contained defects ranging from partial to total obstruction secondary to intraluminal fibrosis within the intramural, isthmic, and ampullary segments in the remaining 35 tubes (56%). Falloposcopy provides a nonincisional modality for defining the normal and abnormal surface anatomy of the tubal epithelium.

The effect of growth factors on the proliferation of human endometrial stromal cells in culture

OBJECTIVE Development of ectopic implants of endometriosis is associated with both an inflammatory response by macrophages and endometrial stromal cell proliferation. Macrophages are capable of releasing a variety of inflammatory mediators, including growth factors. To assess the impact of such factors on endometrial tissue, we have studied the effects of recombinant growth factors, fibroblast growth factor, epidermal growth factor, transforming growth factor-alpha, and inflammation mediators transforming growth factor-beta, and tumor necrosis factor-alpha on human endometrial stromal cell proliferation. STUDY DESIGN Increasing concentrations of these compounds were added to cultures of primary, secondary, and long-term stromal cells and the cells were harvested at 24, 48, and 72 hours. RESULTS Epidermal growth factor, transforming growth factor-alpha, transforming growth factor-beta, and fibroblast growth factor induced a statistically significant, dose-dependent increase in stromal cell thymidine uptake of 1.5- to fivefold. The cytokine tumor necrosis factor had no effect alone, but the combination of fibroblast growth factor and tumor necrosis factor had a synergistic effect, increasing cell proliferation 25% to 84% over fibroblast growth factor alone. CONCLUSION The stromal cell response to a wide range of cell growth effectors and the potential of mediators like tumor necrosis factor-alpha to synergize suggest that such macrophage-secretory products may contribute to proliferation of endometrial implants in vivo.

Add-back therapy and gonadotropin- releasing hormone agonists in the treatment of patients with endometriosis: can a consensus be reached?

OBJECTIVE To reach a consensus on the role of add-back therapy for patients with endometriosis administered GnRH agonists (GnRH-a). DESIGN Results of consensus conference reviewing MEDLINE search of English language abstracts of both prospective and retrospective series. SETTING Consensus conference of 31 specialists in gynecologic surgery and reproductive endocrinology. PATIENT(S) Patients with symptomatic endometriosis who were candidates for GnRH-a therapy in treatment courses ranging in duration from 6 to 12 months. INTERVENTION(S) Oral steroidal and nonsteroidal add-back regimens. MAIN OUTCOME MEASURE(S) Alteration in painful symptoms, extent of disease, vasomotor symptoms, bone mineral density, and serum lipid profile. RESULT(S) When added to GnRH-a for 6 months, both 2.5 mg of norethindrone and 0.625 mg of conjugated equine estrogens with 5 mg/d of medroxyprogesterone acetate provide effective relief of vasomotor symptoms and decrease but do not eliminate bone mineral density loss. During 12 months of GnRH-a therapy, bone mineral density loss is eliminated effectively with an add-back of 5 mg of norethindrone acetate alone or in conjunction with low-dose conjugated equine estrogens. Organic bisphosphonates also may play a role. CONCLUSION(S) In patients with symptomatic endometriosis, the efficacy of GnRH agonists may be preserved and therapy prolonged while overcoming hypoestrogenic side effects with the use of appropriate add-back regimens.