Embryo transfer: techniques and variables affecting success.

OBJECTIVE: To review the literature on the variables affecting embryo transfer success or failure and to define technical factors associated with optimal outcome. DESIGN: Literature review. RESULTS: Avoidance of blood, mucus, bacterial contamination, excessive uterine contractions, and trauma to the endometrium is associated with optimal pregnancy and implantation rates after transcervical embryo transfer. A trial transfer, ultrasonographic guidance, and use of "soft" catheters appear to facilitate successful embryo transfer. CONCLUSION: An understanding of the variables associated with embryo transfer success together with adherence to techniques shown to facilitate atraumatic embryo transfer will enhance the efficiency of IVF by maximizing embryo implantation.

Laparoscopic management of hydrosalpinges before in vitro fertilization-embryo transfer: salpingectomy versus proximal tubal occlusion.

OBJECTIVE: To compare ovarian response and IVF-ET cycle outcome in patients with hydrosalpinges managed by either laparoscopic salpingectomy or proximal tubal occlusion. DESIGN: Retrospective analysis. SETTING: Tertiary-care assisted reproductive technology program. PATIENT(S): One hundred four consecutive fresh IVF-ET cycles in 94 patients with tubal-factor infertility. INTERVENTION(S): Laparoscopic salpingectomy (group 1: 35 cycles) or bipolar proximal tubal occlusion (group 2: 17 cycles), controlled ovarian hyperstimulation, and IVF-ET. Control groups consisted of both tubal-factor patients without hydrosalpinges (group 3: 37 cycles) and those with prior bilateral tubal ligation for sterilization (group 4: 15 cycles). MAIN OUTCOME MEASURE(S): Uterine artery Doppler flow, controlled ovarian hyperstimulation response, and implantation and clinical pregnancy rates. RESULT(S): There were no differences in mean uterine artery pulsatility indices or ovarian response among any of the groups. A trend toward a higher cycle cancellation rate in group 1 did not approach statistical significance. Clinical pregnancy and implantation rates were not significantly different between group 1 (57.1%, 29.2 +/- 5.9%, respectively) and group 2 (46.7%, 19.4 +/- 6.1%, respectively) or compared with those of controls. CONCLUSION(S): [1] Management of hydrosalpinges by laparoscopic salpingectomy or bipolar proximal tubal occlusion yielded statistically similar responses to controlled ovarian hyperstimulation and IVF-ET cycle outcome. [2] The latter approach may be preferable in patients who present with dense pelvic adhesions and easy access only to the proximal fallopian tube.

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.

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.

Role of GnRH agonists in managing proximal fallopian tube obstruction.

OBJECTIVE: To assess the response of proximal fallopian tube obstruction to a medically induced hypoestrogenic state after control for spasm at the uterotubal ostium. STUDY DESIGN: This was a prospective, randomized, placebo-controlled, pilot study in a tertiary care, university-affiliated infertility practice. Twenty-one infertile women with unilateral or bilateral proximal tubal obstruction previously diagnosed by standard hysterosalpingography or laparoscopic chromotubation were randomized into two groups in a 2:1 design. Group I, 14 patients (27 occluded tubes), was administered a depot preparation of the gonadotropin-releasing hormone (GnRH) agonist leuprolide acetate, 3.75 mg intramuscularly every 28 days. Group II, seven patients (11 occluded tubes), was administered a placebo. Follow-up hysterosalpingography was performed after administration of the antispasmodic glucagon within four weeks of completion of the protocol. RESULTS: Evidence of ovarian suppression was confirmed within four weeks in group I. A trend toward higher posttherapy patency rates was noted in group I (74.7% vs. 40%). The lack of statistical significance may have been a function of sample size. Similarly, spontaneous intrauterine pregnancy rates were also higher in GnRH agonist-treated patients (35.1% vs. 16.6%, P < .05). Tubal patency rates were significantly greater in patients with documented estrogen-sensitive disorders who received the agonist (75% vs. 20%, P < .05) CONCLUSION: Proximal tubal obstruction may be an estrogen-sensitive phenomenon in a subset of infertile patients. The administration of GnRH agonists may successfully overcome this state and result in enhanced conception rates.

Microendoscopy of the human fallopian tube.

Advances in fiberoptic technology make it possible to evaluate the tubal lumen endoscopically. Two basic procedures are salpingoscopy and falloposcopy. The former is a transfimbrial approach allowing visualization from the ampullary-isthmic junction to the fimbriae. The latter is a transcervical approach allowing assessment of the tubal lumen from the uterotubal ostium to the fimbriae. Both may be performed without general anesthesia. The procedures provide more sensitive information than laparoscopy with chromotubation or hysterosalpingography alone. Findings provide a strong correlation with conception. Technical shortcomings make falloposcopy more difficult than the more straightforward transfimbrial technique. With more widespread acceptance, endoscopic evaluation of the fallopian tube may become a standard component of the infertility evaluation.

Falloposcopy.

The role of the human fallopian tube in reproduction is more than a passive conduit. This organ is involved in oocyte pick-up, fertilization, and embryo transport. Metabolic substrates, cytokines, and immunoglobulins have been identified within the tubal lumen. Complex and coordinated endocrine secretions, neuromuscular activity, and cilial action are required for successful tubal function.

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

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.

Is intracytoplasmic sperm injection necessary for couples undergoing in vitro fertilization-embryo transfer with normal semen analyses but failing hamster egg penetration assays?

PURPOSE: Our purpose was to assess whether in vitro fertilization (IVF)-embryo transfer (ET) candidate couples with basically normal semen analyses but failing zona-free hamster egg penetration assay (HEPA) scores benefit from intracytoplasmic sperm injection (ICSI). METHODS: Twenty consecutive IVF candidate couples with normal-borderline semen analyses and failing HEPA scores were recruited. Mature oocytes obtained from each woman were randomly divided between ICSI (group I; n = 126 oocytes) and standard insemination techniques (group II; 138 oocytes). Fertilization (two pronuclei) and cleavage (2-4 cells) rates were assessed for both groups. RESULTS: There were no statistically significant differences between the two groups with respect to (mean +/- standard error of the mean) fertilization (group I, 63.1 +/- 7.75; group II, 77.8 +/- 4.7%) or cleavage (group I, 87.3 +/- 2.4%; group II, 91.2 +/- 3.5%) rates. CONCLUSIONS: ICSI is not beneficial for IVF-ET when sperm samples demonstrate a failing HEPA score but have normal or minimally compromised semen analysis parameters.

Add-back therapy: extending safety and efficacy of GnRH analogues in the gynecologic patient.

GnRH analogues have been demonstrated to be effective medical therapy for symptomatic endometriosis. The use of these agents has been limited to 6 months due to hypoestrogenic side effects. A variety of steroidal and nonsteroidal add-back regimens have been used in an effort to eliminate such side effects while maintaining efficacy in order to enhance compliance, safety and duration such side effects while maintaining efficacy in order to enhance compliance, safety and duration of administration of these agents. Only 3 regimens have been shown to be efficacious in prolonging analogue use beyond 6 months by reducing vasomotor symptoms as well as preventing significant bone mineral density loss. These include daily norethindrone acetate 5 mg alone or in conjunction with conjugated equine estrogens 0.625 mg daily, as well as norethindrone 2.5 mg daily in conjunction with an organic bisphosphonate. With further investigation, such regimens may allow safe prolongation of GnRH analogue use without sacrificing efficacy in those endometriosis patients with severe pelvic pain.

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.

Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group.

OBJECTIVE: To evaluate the efficacy and safety of a GnRH agonist, leuprolide acetate depot, alone and in combination with three hormonal add-back regimens in the management of endometriosis-associated pelvic pain. METHODS: Two hundred and one patients were enrolled in this multicenter, randomized, double-blind, 1-year trial. All patients were given an intramuscular injection of leuprolide acetate depot 3.75 mg every 4 weeks. Patients were assigned to one of four treatment groups: Group A received placebos for progestin and estrogen, group B received norethindrone acetate 5 mg daily and placebo for estrogen, group C received norethindrone acetate 5 mg and conjugated equine estrogens 0.625 mg daily, and group D received norethindrone acetate 5 mg and conjugated equine estrogens 1.25 mg daily. Pelvic pain scores were assessed monthly, and bone density was measured after 24 and 52 weeks. RESULTS: By week 8, all four groups showed significant improvement in pelvic pain scores compared with baseline levels. A higher proportion of group D patients terminated the study prematurely due to a lack of improvement in symptoms. Group A experienced a 6.3 +/- 2.3% (P < or = .001) loss in bone density after 52 weeks of treatment, whereas bone density was preserved in all three add-back groups. CONCLUSION: The use of leuprolide acetate depot in combination with norethindrone acetate 5 mg alone, or with norethindrone acetate and conjugated equine estrogens 0.625 mg, provides effective suppression of pelvic pain symptoms associated with endometriosis while protecting against bone loss.

Incomplete androgen and progesterone suppression following midluteal GnRHa prior to controlled ovarian hyperstimulation for IVF-ET.

PURPOSE: We aimed to determine if midluteal GnRH agonist (GnRHa) use prior to controlled ovarian hyperstimulation (COH) results in uniform progesterone and androgen suppression and whether elevations of these hormones occurring early in follicular development may adversely effect the outcome of IVF-ET. METHODS: Forty-four COH cycles using midluteal GnRHa were evaluated. Serum gonadotropins (LH and FSH) and gonadal steroids (E2, A, P4, and T) were measured after 10 days of GnRHa administration [cycle day 31 (CD 31)] and again on the day of hCG administration, following COH. Cycle outcomes evaluated were the number of oocytes retrieved, morphologic grade, fertilization, implantation, pregnancy, and spontaneous abortion rates. RESULTS: Endogenous serum FSH was uniformly suppressed (6.32 +/- 0.47 IU/L) on CD 31, however, LH was not (23.76 +/- 0.76 IU/L). Five and four tenths percent of cycles demonstrated low-level P4 elevations (> or = 0.9 ng/ml), 24.4% demonstrated serum androstenedione levels > or = 600 pg/ml, and 39% of cycles were characterized by serum T levels > or = 200 pg/ml despite evidence of E2 suppression (< or = 30 pg/ml) and the absence of follicular growth by sonography. LH levels were not predictive of incomplete P4 or androgen suppression. Elevations of either P4, A, or T occurring early in the follicular phase were not found to correlate with an impairment in clinical cycle outcome. CONCLUSIONS: Midluteal GnRHa use prior to COH may result in incomplete suppression of circulating progresterone and androgens. However, these relative elevations, occurring early in the development of the follicular cohort, did not appear to affect IVF cycle outcome adversely.

Multicenter feasibility study of a new coaxial falloposcopy system.

We compared falloposcopy employing a new coaxial system with traditional laparoscopic chromotubation and hysterosalpingography in a prospective, multicenter clinical trial at five tertiary infertility centers. Based on findings at hysterosalpingography or laparoscopic chromotubation, the 16 women (22 tubes) in group 1 had a presumed diagnosis of proximal tubal obstruction, and the 4 (7 tubes) in group 2 had unexplained infertility. Cannulation was successfully achieved in 83.3% of tubes. In group 1, 85% (17/20) of visualized tubes were patent and 35% (7/20) were normal. In group 2, 40% (2/5) of visualized tubes were abnormal. Management was changed in 52.4% of women as a result of falloposcopic findings. Falloposcopy with this new coaxial system allows improved visualization with less bulky and less traumatic instruments. The system provides valuable information regarding the fallopian tube lumen that correlates poorly with that obtained with more traditional techniques.

Spontaneous pregnancies despite failed attempts at ovulation induction in a woman with latrogenic premature ovarian failure.

BACKGROUND: Women with premature ovarian failure may conceive spontaneously or following different regimens of ovulation induction. CASE: A 29-year-old woman with eight years of hypergonadotropic hypogonadism following chemotherapy and radiotherapy for Hodgkin's disease conceived spontaneously and spontaneously aborted after discontinuation of estrogen replacement. Subsequently she underwent pituitary gonadotrope downregulation and attempted controlled ovarian hyperstimulation without an ovarian response or follicular development. Despite this failure, she conceived spontaneously on two occasions, resulting in a live-born infant and an ongoing pregnancy. CONCLUSION: Cases of hypergonadotropic hypogonadism may not be permanent or irreversible. Interventional regimens may fail to induce ovulation despite the presence of residual oocytes capable of recruitment and fertilization.

Correlation between salpingoscopic and laparoscopic staging in the assessment of the distal fallopian tube.

OBJECTIVE: To correlate the severity and extent of intraluminal tubal abnormalities assessed by transfimbrial salpingoscopy with traditional criteria for evaluating distal tubal disease at laparoscopy. DESIGN: Prospective 2-year clinical trial with long-term follow-up. SETTING: University-affiliated tertiary care reproductive medicine and surgery practice. PATIENTS: Fifty-five infertile women with suspected distal tubal disease or unexplained infertility. INTERVENTIONS: Transfimbrial salpingoscopy was performed at the time of laparoscopy and terminal neosalpingostomy when appropriate. Salpingoscopic and laparoscopic findings of 91 fallopian tubes were scored independently. RESULTS: No correlation between laparoscopic and salpingoscopic findings was noted in group I tubes (n = 51) categorized as having minimal disease or no pathology by traditional staging. In contrast, a strong correlation was noted between findings obtained from these two techniques in group II tubes (n = 40) diagnosed as having moderate-to-severe tubal disease at laparoscopy. Intrauterine pregnancy was achieved in 38.9% (7/18) of patients with mean salpingoscopy scores < or = to 12 versus 3.8% (1/26) of patients with mean scores > 12. Life-table analyses of cumulative estimated pregnancy rates were significantly different between the groups. CONCLUSIONS: Fallopian tubes with minimal pathology appreciated at laparoscopy may have more significant intraluminal disease appreciated at salpingoscopy. In contrast, laparoscopic and salpingoscopic findings do correlate well in cases of more severe distal disease. Elevated mean salpingoscopy scores are associated with an extremely poor prognosis for conception.

Short-term endocrine response to gonadotropin-releasing hormone agonist initiated in the early follicular, midluteal, or late luteal phase in normally cycling women.

OBJECTIVE: To determine short-term pituitary and ovarian hormonal responses to GnRH agonist (GnRH-a) administered during various phases of the menstrual cycle, in the absence of controlled ovarian hyperstimulation (COH), to determine its independent effect on hormonal parameters previously demonstrated to influence assisted reproductive technology cycle outcome. DESIGN: Prospective, randomized, controlled crossover study of five regularly cycling women. The GnRH-a, leuprolide acetate (LA), was administered 1 mg SC daily for 5 days beginning on cycle day 3 (early follicular); 8 days post-LH surge (midluteal); or 13 days post-LH surge (late-luteal). SETTING: Clinical research unit at a tertiary care medical center. MAIN OUTCOME MEASURES: Serum gonadotropins (LH and FSH) and gonadal steroids (E2, estrone [E1], P, A, and T) measured daily during GnRH-a administration begun in the early follicular, midluteal, or late luteal phase of the menstrual cycle. Gonadotropin pulse amplitude and frequency were determined after frequent serum sampling on the 2nd day of GnRH-a administration in each treatment cycle. RESULTS: Serum LH elevations, 4- to 10-fold greater than observed for FSH, did not differ by cycle day of GnRH-a initiation. Initial increases in FSH did not differ by cycle day, however, early follicular initiation resulted in a more pronounced suppression of FSH. Mean LH pulse amplitude and frequency increased to a similar extent in all three groups, however, FSH pulse amplitude and frequency varied significantly by cycle day of GnRH-a initiation. Gonadotropin-releasing hormone agonist initiated in the early follicular phase resulted in significant increases in E2, E1, and P levels compared with both midluteal or late luteal. Increases in serum androgens were significantly greater after early follicular and late luteal initiation as compared with midluteal GnRH-a initiation. CONCLUSIONS: Relative FSH suppression and marked androgen elevations in both late luteal and early follicular groups, which may have potential detrimental effects on oocytes of the developing cohort, suggest little advantage of late luteal or early follicular over midluteal initiation of GnRH-a for COH.

Steroidal and nonsteroidal "add-back" therapy: extending safety and efficacy of gonadotropin-releasing hormone agonists in the gynecologic patient.

OBJECTIVE: To assess the efficacy of various steroidal and nonsteroidal add-back regimes in ameliorating hypoestrogenic side effects of long-term GnRH agonist (GnRH-a) therapy in gynecologic patients. DESIGN: English language literature review. PATIENTS: Gynecologic patients administered GnRH-a as therapy for ovarian hyperandrogenism, premenstrual syndrome, dysfunctional uterine bleeding, uterine leiomyomata, and symptomatic endometriosis. INTERVENTIONS: Steroidal and nonsteroidal add-back regimes including estrogens with progestins, progestins alone, and progestins with organic bisphosphonates in combination with various GnRH-a for > or = 6 months of therapy. MAIN OUTCOME MEASURES: Vasomotor symptoms, bone density changes, lipid profiles, alterations in presenting symptoms, and disease state. RESULTS: Estrogens in combination with progestins were efficacious as add-back in the management of ovarian hyperandrogenic states, dysfunctional uterine bleeding, premenstrual syndrome, and leiomyomata. Medroxyprogesterone acetate alone is ineffective as add-back for treatment of endometriosis or leiomyomata. Norethindrone is effective as add-back in the management of endometriosis but not leiomyomata, although high doses alter lipid profiles in an undesirable fashion. Organic bisphosphonates show great promise in preserving bone density without other untoward effects. CONCLUSIONS: No single add-back regime is appropriate for all gynecologic indications for GnRH-a. Ideal protocols preserve the efficacy of agonists while suppressing associated vasomotor symptoms and bone density loss.

Prolonged gonadotropin-releasing hormone agonist treatment of symptomatic endometriosis: the role of cyclic sodium etidronate and low-dose norethindrone "add-back" therapy.

OBJECTIVE: To examine the safety and efficacy of combining cyclic sodium etidronate and low-dose norethindrone with a long-acting GnRH agonist (GnRH-a) for prolonged therapy of symptomatic endometriosis. DESIGN: Prospective randomized open label study. SETTING: Tertiary care university-affiliated reproductive medicine program. PATIENTS: Nineteen regularly cycling women with laparoscopically diagnosed symptomatic endometriosis and 18 regularly cycling untreated controls without endometriosis. INTERVENTIONS: All patients received a depot preparation of the GnRH-a leuprolide acetate IM monthly for 48 weeks. Group I patients (n = 10) received supplemental sodium etidronate cycled with calcium carbonate as well as 2.5 mg norethindrone daily. Group II patients (n = 9) received only supplemental 10 mg norethindrone daily. Group III volunteers (n = 18) were untreated and followed for bone density changes. MAIN OUTCOME MEASURES: Disease extent at follow-up laparoscopy; pain, vasomotor, and vaginal symptom scores; bone mineral density (serial dual-energy roentgenogram absorptiometry scans); serum estrogens, lipids, and glucose and insulin response to glucose challenge. RESULTS: Painful symptoms and extent of endometriosis were reduced in both treatment groups. Despite maintenance of a chronically hypoestrogenic state for 48 weeks, no changes in bone density over time or in comparison to group III untreated controls were noted. Similarly, no evidence of significant vasomotor symptoms were reported in either treatment group. However, adverse changes over time in circulating low-density lipoprotein (LDL) cholesterol and apolipoprotein A1 levels as well as the ratio of high-density lipoprotein to LDL were noted only in group II. CONCLUSIONS: The combination of cyclic sodium etidronate and low-dose norethindrone with a long-acting GnRH-a served to safely prolong medical therapy of symptomatic endometriosis. Clinical efficacy was preserved while prophylaxis against significant hypoestrogenic side effects was achieved.