p27 and its ubiquitin ligase Skp2 expression in endometrium of IVF patients with repeated hormonal stimulation.

This preliminary study examined a possible effect of long duration repeated hormonal stimulation on the endometrium using a molecular tool. The expression of the hormone stimulated, cell cycle regulators, p27 and its ligase S-phase kinase-interacting protein2 (Skp2), were assessed in 46 endometrial samples of patients who underwent repeated IVF cycles (3-21). Skp2 protein is usually undetectable in normal tissue and can be demonstrated only in rapidly dividing cells. Samples from non-stimulated, normal cycling women served as control group A. Samples of endometrial carcinoma served as control group B. In secretory endometrium, the expression of p27 was found to be lower and Skp2 higher in the study group compared with control group A. Moreover, in 25% of patients of the study group, Skp2 expression was significantly higher (P < 0.05) compared with control group A, reaching concentrations demonstrated in endometrial carcinoma. The findings of this study suggest that repeated hormone stimulation cycles may disrupt endometrial physiology, potentially towards abnormal proliferation. These changes in protein expression are described for the first time in IVF patients and should be further investigated.

GnRH agonist trigger and a freeze-all strategy to prevent ovarian hyperstimulation syndrome: a retrospective study of OHSS risk and pregnancy rates.

AIMS: To analyse the data from all controlled ovarian hyperstimulation antagonist cycles that used an agonist trigger and a freeze-all strategy to quantify the risk of ovarian hyperstimulation syndrome (OHSS) and subsequent pregnancy rates. MATERIALS AND METHODS: A retrospective study of all women attending fertility clinics at IVF Australia, Sydney, undergoing controlled ovarian hyperstimulation (COH) using an antagonist protocol that had a subsequent gonadotropin-releasing hormone (GnRH) agonist trigger and freezing of all oocytes or embryos. The primary outcome measure was to determine the rate of OHSS. The secondary outcome measure was the clinical pregnancy rate. RESULTS: We collected data for 123 women. 25.2% were undergoing oocyte freezing and 74.8% underwent embryo freezing. There were no cases of OHSS, either early or late onset. The pregnancy rate was 31.7% after the first frozen cycle transfer with a cumulative pregnancy rate of 50% after two frozen embryo transfers. CONCLUSION: Our results support the hypothesis that a GnRH agonist trigger and a freeze-all approach prevents OHSS with a good pregnancy rate.

Elevated progesterone in GnRH agonist down regulated in vitro fertilisation (IVFICSI) cycles reduces live birth rates but not embryo quality.

OBJECTIVE: To assess the impact of pre-hCG elevated progesterone on live birth outcomes during GnRH agonist long down regulated protocol assisted reproduction cycles. DESIGN: Retrospective cohort study. SETTING: Single Centre Private IVF Clinic. PATIENTS: A total of 582 consecutive cycles of IVF/ICSI in 2003. INTERVENTIONS: All patients underwent a long down-regulation protocol, controlled ovarian stimulation and IVF/ICSI. Serum progesterone concentrations were measured just prior to HCG administration. 253 patients were followed to 2009 for outcomes of their frozen embryo cycles. MAIN OUTCOME MEASURE: Live birth rate in fresh and frozen cycles. RESULTS: Patients in the upper quartile pre-hCG progesterone concentration (≥ 5.4 pmol/L) had a higher final estradiol level, more oocytes collected and more usable embryos, when compared to those with lower quartiles. They also had lower live birth rates per cycle started (21.9% vs. 15%, P < 0.05). However, live birth rates from frozen embryo cycles were not significantly different between the groups. CONCLUSIONS: Pre-hCG progesterone elevation leads to lower live birth rates in stimulated IVF cycles. Live birth rates achieved with frozen embryos in the high progesterone cycles suggest, that pre-hCG progesterone elevation negatively affects endometrial receptivity without adversely affecting embryo quality.

A randomised controlled trial of 300 versus 225 IU recombinant FSH for ovarian stimulation in predicted normal responders by antral follicle count.

OBJECTIVE: To test the hypothesis that among women predicted to have a normal ovarian response, ovarian stimulation using 300 IU follicle-stimulating hormone (FSH) results in the retrieval of more mature oocytes than 225 IU during in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) treatment. DESIGN: Prospective randomised controlled study. SETTING: University-based assisted conception unit. POPULATION: A cohort of 131 women predicted to have a normal ovarian response to gonadotrophin stimulation, based on antral follicle count. METHODS: Subjects undergoing their first cycle of IVF/ICSI were randomised to receive a fixed daily dose of 300 (experimental arm) or 225 IU (control arm) of recombinant FSH (Gonal-F). MAIN OUTCOME MEASURES: Number of mature oocytes retrieved and live birth rates. RESULTS: The number (mean +/- standard deviation) of mature oocytes retrieved (8.2 +/- 5.0 versus 9.0 +/- 4.8, for 300 and 225 IU, respectively; P = 0.34) was similar in each group. There were no differences between the 300- and 225 IU arms in live birth rates (31 versus 41%, respectively; P = 0.25), cycle cancellations resulting from insufficient ovarian response (0 versus 6.1%, respectively; P = 0.12), and prevalence of moderate (3.1 versus 3.0, respectively; P = 1.0) and severe (0 versus 1.5%, respectively; P = 1.0) ovarian hyperstimulation syndrome. CONCLUSIONS: The use of a higher daily dose of 300 IU of recombinant FSH for ovarian stimulation does not improve the number of mature oocytes retrieved, or live birth rates, among women with a predicted normal response during conventional IVF/ICSI.

Prospective randomised trial comparing gonadotrophin-releasing hormone analogues with triple tourniquets at open myomectomy.

OBJECTIVE: To compare intra-operative blood loss with triple tourniquets to occlude uterine blood supply against preoperative treatment with gonadotrophin-releasing hormone (GnRH) analogues at open myomectomy. DESIGN: A prospective randomised controlled trial. SETTING: University teaching hospital. POPULATION: Forty women undergoing open myomectomy for symptomatic fibroids. METHODS: Women due to undergo open myomectomy were randomised to either 3 months pre-treatment with a GnRH analogue or the intra-operative application of triple tourniquets (number 1 polyglactin suture [Vicryl Ethicon Inc., Somerville, NJ, USA] tied around the cervix and a size 10 polythene suction catheter tied around the infundibulo-pelvic ligaments) to occlude the uterine blood supply. MAIN OUTCOME MEASURES: The primary outcome measure was intra-operative blood loss. Secondary outcome measures included postoperative blood loss, blood transfusion rate and postoperative morbidity. RESULTS: The two groups were similar in baseline characteristics. An average of 15 and 22 fibroids were removed from the GnRH analogue and tourniquet groups respectively. Intra-operative estimated blood loss was significantly higher in the GnRH analogue group (median 2482 ml, 75% percentile 1744-3151) than when triple tourniquets were used (median 640 ml, 75% percentile 418-881), giving a difference between means of 1842 ml (P<0.001). Similarly, significantly more women required blood transfusion in the GnRH analogue group (70 versus 30%, P<0.025). Postoperative morbidity was similar between the two groups. There were two serious complications in the tourniquet group, but they were not considered to be directly related to occlusion of the uterine blood supply. CONCLUSIONS: Triple tourniquets are significantly more effective than preoperative treatment with GnRH analogues at reducing intra-operative blood loss at open myomectomy.

Successful pregnancy after gonadotropin-releasing hormone analogue and hysteroscopic myomectomy in a woman with diffuse uterine leiomyomatosis.

We report a patient with diffuse uterine leiomyomatosis, who wished to become pregnant. We performed hysteroscopic myomectomy after treatment with nafarelin acetate for 6 months. The patient conceived spontaneously soon after hysteroscopic myomectomy, and delivered a 2,798-g healthy baby.

Endometriosis and its treatment with danazol or lupron in relation to ovarian cancer.

PURPOSE: It has been hypothesized that circulating androgens may be involved in the development of ovarian cancer. The androgenic medication, danazol, and the antiandrogenic medications, leuprolide and nafarelin, are commonly used in the treatment of endometriosis. We assessed the associations between the use of these medications and ovarian cancer. EXPERIMENTAL DESIGN: We pooled information on self-reported use of danazol and leuprolide/nafarelin from two population-based case-control studies of incident ovarian cancer, comprising 1373 cases and 1980 controls. Odds ratios for the association between danazol and ovarian cancer, and leuprolide/nafarelin and ovarian cancer were adjusted for age, parity, oral contraceptive use, and family history of ovarian cancer. These analyses were repeated among the 120 cases and 124 controls who reported having had endometriosis. RESULTS: Danazol users (n = 19) were at a significantly elevated 3.2 fold (95% confidence interval, 1.2-8.5) risk of developing ovarian cancer, whereas leuprolide/nafarelin users (n = 23) were not at significantly elevated risk (odds ratio, 1.0; 95% confidence interval, 0.4-2.4). Similar results were obtained among the subset of women with endometriosis. CONCLUSIONS: Danazol, but not leuprolide/nafarelin, increased the risk of ovarian cancer. This supports the hypothesis that androgen excess may be associated with the development of ovarian cancer.

A randomized, parallel, comparative study of the efficacy and safety of nafarelin versus danazol in the treatment of endometriosis in Taiwan.

BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of nafarelin, a gonadotropin-releasing hormone (GnRH) analogue, versus danazol in the treatment of women with endometriosis in Taiwan. METHODS: Fifty-nine women with laparoscopically and pathologically confirmed endometriosis were randomized to receive nafarelin or danazol for 180 days. Efficacy was assessed from mean changes in laparoscopy score (LS) and total symptom severity score (TSSS). Adverse events (AEs) and laboratory parameters, including hematology, hepatic function, blood pressure, and lipid levels, were monitored for safety evaluations. RESULTS: All demographic and baseline factors, except body weight, were comparable between the 2 treatment groups. Both nafarelin and danazol satisfactorily resolved pelvic tenderness, induration, pelvic pain, dysmenorrhea and dyspareunia. No significant differences were noted in efficacy endpoints between nafarelin and danazol regarding LS and TSSS at 90 and 180 days of treatment. No significant difference was observed between the 2 groups regarding the overall incidence of AEs, except for laboratory-related AEs. However, nafarelin tended to have less impact than danazol on aspartate transaminase and alanine transaminase, and nafarelin was better tolerated than danazol regarding changes in lipid profiles. Both treatments had little or no effect on hematologic parameters. CONCLUSION: Nafarelin and danazol demonstrated similar clinical efficacy, but nafarelin was associated with fewer laboratory changes and a stable lipid profile, relative to danazol. Moreover, intranasally administered nafarelin is noninvasive, and may be a more comfortable and safer alternative to slow-release injectable GnRH agonists. Based on this study, we suggest that nafarelin, like other GnRH analogues, may be a treatment of choice for Taiwanese women with endometriosis. However, direct comparative studies of nafarelin with slow-release injectable GnRH agonists are now required.

Increases in bone mineral density after discontinuation of daily human parathyroid hormone and gonadotropin-releasing hormone analog administration in women with endometriosis.

Intermittent PTH administration increases spinal bone mineral density (BMD) and prevents bone loss from the hip and total body in young women treated with a long acting GnRH analog for endometriosis. To establish whether these beneficial effects on BMD persist after PTH administration is discontinued, we remeasured BMD and biochemical markers of bone turnover in 38 women with endometriosis who had been treated with a GnRH analog alone (nafarelin acetate; 200 microg, intranasally, twice daily; n = 23; group 1) or who had received nafarelin plus human PTH-(1-34) (40 microg/day, s.c.; n = 15; group 2) for 6-12 months 1 yr after therapy was completed. Cyclic menstrual function returned promptly after nafarelin therapy was discontinued. In group 1, BMD increased significantly at all sites [P < 0.001 for the anterior-posterior (AP) and lateral spine; P = 0.014 for the femoral neck; P = 0.004 for the trochanter], except the proximal radius (P = 0.065) and total body bone density (P = 0.069) after nafarelin therapy was stopped. In group 2, BMD increased significantly at the AP spine (P < 0.001), lateral spine (P = 0.012), femoral neck (P = 0.002), and trochanter (P = 0.029) after nafarelin therapy was stopped. BMD of the spine in the AP projection increased more in group 2 and than in group 1 after therapy was stopped (P = 0.045). Despite these increases after discontinuation of nafarelin therapy, BMD was still significantly below baseline values at the AP spine (P < 0.001) and femoral neck (P = 0.006) and tended to be lower than baseline values at the trochanter (P = 0.057) and total body (P = 0.101) at the end of the 1-yr follow-up period in group 1. In contrast, BMD was significantly above baseline values at the AP and lateral spine (P < 0.001) sites and was similar to baseline values at the other skeletal sites at the end of the 1-yr follow-up period in group 2. Bone turnover returned to baseline values in both groups when therapy was stopped. We conclude that the beneficial effects of PTH on bone persist in women who regain cyclic menstrual function. Although part of the increases in BMD are probably due to restoration of ovarian function, additional increases in BMD most likely represent a further anabolic effect of PTH on bone that is not detected until after PTH administration is stopped.

Recurrent fever associated with progesterone action and persistently elevated serum levels of immunoreactive tumor necrosis factor-alpha and interleukin-6.

We describe two women who suffer from recurrent fever up to 40 C in association with progesterone action and who have continuously elevated serum levels of immunoreactive tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6). In patient 1, recurrent fever began at age 17 yr and has now continued for 11 yr. The patient has had three early pregnancy terminations because of continuous fever and, thereafter, three early pregnancy losses associated with fever. In patient 2, fever first appeared at age 18 yr, and the attacks have now continued for 3 yr. The association between fever and progesterone action is supported by the following facts. 1) The episodes of fever appear in the midluteal phase of the menstrual cycle concomitantly with the highest concentration of serum progesterone. 2) Fever is further exaggerated in early pregnancy. 3) Synthetic progestins induce fever regardless of the day of the menstrual cycle. 4) The progesterone antagonist RU 486 and an agonist of GnRH, nafarelin, are capable of preventing the fever, with no effect on serum cytokine levels. Although the underlying mechanism of elevated TNF alpha and IL-6 levels in our patients remains unknown, the data suggest that these cytokines cooperate with progesterone in exerting a pyrogenic response in the hypothalamic thermoregulatory center.

Localization and quantification of vascular endothelial growth factor messenger ribonucleic acid in human myometrium and leiomyomata.

Vascular endothelial growth factor (VEGF) messenger RNA (mRNA) and VEGF peptide were studied in human myometrium and leiomyomata. Amplification of complementary DNA from myometrium and leiomyomata by the polymerase chain reaction revealed three species of mRNA encoding VEGF: VEGF189, VEGF165, and VEGF121. In situ hybridization demonstrated VEGF mRNA expression throughout the smooth muscle cells of myometrium and leiomyomata. VEGF-like immunoreactivity was also detected in these tissues by immunocytochemistry. Quantification of VEGF mRNA using an RNAse protection assay demonstrated that in normal myometrium, levels of VEGF mRNA are significantly higher in the secretory phase than in the proliferative phase of the cycle. Leiomyomata did not have significantly different levels of VEGF mRNA compared with normal myometrium. In untreated leiomyomata, there was no significant difference between VEGF mRNA levels in the proliferative and secretory phases of the cycle. Leiomyomata from women treated with a GnRH anlog did not have significantly different levels of VEGF mRNA from untreated leiomyomata.

Comparison of a gonadotropin-releasing hormone agonist and a low dose oral contraceptive given alone or together in the treatment of hirsutism.

Chronic GnRH agonist therapy lowers androgens and decreases androgen-dependent hair shaft diameter, but the resulting induction of hypoestrogenemia has limited its usefulness as a single agent. Estrogen- and progestin-containing oral contraceptives also reduce circulating androgen levels and are commonly used empirically for the treatment of hirsutism, but have not been evaluated in a blinded randomized controlled fashion. The present study is the first double masked trial to evaluate the combination use of a GnRH agonist and an estrogen-containing oral contraceptive and tests our hypothesis that these could synergistically reduce androgen levels and suppress hormone-dependent hair growth while avoiding the symptoms and risks of agonist-induced hypoestrogenemia. We enrolled 64 women in a 24-week blinded randomized controlled trial to compare placebo, nafarelin (NAF; 400 micrograms, intranasal spray, twice daily), norethindrone (1 mg), and ethinyl estradiol (NOR 1/35; 0.035 mg, daily, for 3 of 4 weeks), or combined use of NAF and NOR 1/35 for 24 weeks. At baseline and every 8 weeks, we measured gonadotropins, estrogens, androgens, and hair growth. Bone density was assessed by dual energy x-ray adsorptiometry, and hot flashes were measured objectively. Baseline total testosterone (T), free T, percent free T, and sex hormone-binding globulin-binding capacity were similar among groups. With treatment, significant reductions (P = 0.01) in total T were seen with combination and NAF only therapy. Significant increases (P < 0.001) in the sex hormone-binding globulin-binding capacity were seen in women given NOR 1/35 alone or in combination with NAF. Free T levels decreased to approximately half of baseline levels with combination treatment (17.9 to 6.4 nmol/L; P < 0.001) and NOR 1/35 alone (20.8 to 10.2 nmol/L; P < 0.001). There was a significant decrease in hair shaft diameter after combination therapy (P < 0.05) that was not seen with either agent alone. Combination therapy also prevented the hot flashes and bone loss that occurred with agonist alone. In summary, our results demonstrate that combination GnRH agonist and low dose oral contraceptive therapy is more effective than either agent alone in the treatment of hirsutism and avoids the hypoestrogenic complications that occur with agonist only therapy.

The luteinizing hormone-releasing hormone-secreting hypothalamic hamartoma is a congenital malformation: natural history.

The LHRH-secreting hypothalamic hamartoma (HH), a congenital malformation consisting of a heterotopic mass of nervous tissue that contains LHRH neurosecretory neurons attached to the tuber cinereum or the floor of the third ventricle, can cause true or central precocious puberty (TPP). We have suggested that it functions as an ectopic LHRH pulse generator independent of the central nervous system inhibitory mechanism that normally restrains the hypothalamic LHRH pulse generator. TPP associated with a hamartoma has all of the hormonal hallmarks of puberty, including a pubertal pattern of pulsatile LH and a pubertal plasma LH response to LHRH administration. Little is known about the natural history of HH. We present long term data on 10 children (5 females and 5 males) with TPP due to HH. Physical signs of puberty were observed at a mean age of 2.2 +/- 1.6 yr (range, 0.5-5.1). Two of 10 had a pedunculated mass, and 8 of 10 had a sessile mass. The hamartoma varied in diameter from 4-25 mm and did not change with time (3.5-8.7 yr). Four patients have a seizure disorder, 3 with gelastic seizures (1 with mental retardation) and 1 with tonic-clonic seizures. The shape of the hamartoma, sessile or pedunculated, did not correlate with the occurrence of seizures. At presentation with sexual precocity, the mean height SD for chronological age was +3.5 +/- 0.4, the mean height SD for bone age was -1.9 +/- 0.4, and the mean bone age SD for chronological age was +6.8 +/- 0.7. Baseline data were comparable to those of 10 females with idiopathic TPP. Nine of 10 HH patients and all idiopathic TPP patients were treated with a LHRH agonist. The response to therapy was excellent in both groups and indistinguishable. Nine of 10 HH children attend school regularly and, aside from those with seizures, have no neurological handicap. While surgical resection of the hamartoma has been recommended, it carries an increased risk of morbidity and mortality and, if removal is incomplete, does not arrest the sexual precocity. In our experience, LHRH agonist therapy for TPP due to HH is the preferable approach.

Effects of long-term treatment with the gonadotropin-releasing hormone analog nafarelin in patients with non-functioning pituitary adenomas.

The supposed origin of non-functioning pituitary adenomas (NFPA) from gonadotrophs prompted us to investigate the effects of the gonadotropin-releasing hormone (GnRH) analog nafarelin on hormonal and tumoral parameters in eight patients with NFPA, previously unsuccessfully operated and all hypogonadal. Nafarelin was administered intranasally for 1 year to all patients. Four patients received a dose of 1200 micrograms/day; the remaining four received 800 micrograms/day for 3 months, which was subsequently increased to 1200 micrograms/day. Basal gonadotrophin and alpha-subunit (alpha SU) levels were low-normal. In four patients (nos. 1,2,3,5) nafarelin significantly lowered luteinizing hormone (LH) levels, and also follicle-stimulating hormone (FSH) in three of them (nos. 1,2,3). Persistent FSH stimulation occurred in three patients (nos. 6,7,8), with a transient slight LH increase only in patient no. 8. In one patient (no. 7), alpha SU levels were persistently stimulated. Hormonal responses to an acute GnRH test during nafarelin administration were generally blunted when compared to the pretreatment responses. Immunofluorescence results, obtained before treatment in five adenomas (nos. 2,3,4,6,7), hae been as follows: positive for FSH-beta in all; negative for LH-beta in all, except a few positive cells in case no. 4; positive for alpha SU in three (nos. 2,3,7). No changes of visual field and tumor size occurred in any patient during treatment. However, one patient who showed a persistent increase in FSH levels exhibited left palpebral ptosis after 12 months of therapy and underwent a second transsphenoidal surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Change in C-terminal cross-linking domain of type I collagen in urine, a new marker of bone resorption, during and after gonadotropin-releasing hormone agonist administration.

OBJECTIVE: The major side effect of GnRH agonist (GnRHa) therapy is the reduction of bone mass. To analyze bone resorption by GnRHa, we measured the urinary excretion of C-terminal telopeptides of type I collagen (CTX), a new marker of bone resorption. METHODS: We used a new ELISA for CTX (CrossLaps) in a sample of 18 premenopausal women with leiomyoma who were treated with daily administration of 400 micrograms nafarelin or 900 micrograms buserelin for 16 weeks. RESULTS: Urinary CTX excretion increased significantly during GnRHa treatment and then decreased at 12 and 24 weeks after the cessation of GnRHa therapy. Whereas the excretory profile of CTX during GnRHa therapy was almost similar to that of pyridinoline (Pyr) or deoxypyridinoline (D-Pyr), both biochemical markers of bone resorption, the magnitude of the change in CTX was significantly greater than that in Pyr or D-Pyr. CONCLUSIONS: These results indicate that CTX could be a more sensitive marker for bone resorption than the currently used biochemical markers, and that CrossLaps ELISA is useful for therapeutic monitoring during and after GnRHa treatment.

Urinary N-telopeptides to monitor bone resorption while on GnRH agonist therapy.

OBJECTIVES: To assess the utility of urinary cross-linked N-telopeptides in monitoring bone resorption and predicting bone loss during GnRH agonist administration. METHODS: Ninety patients who were prescribed GnRH agonist therapy for 3-6 months for treatment of endometriosis, leiomyomas or other gynecologic disorders participated in this prospective multicenter study. N-telopeptides, serum estradiol (E2), and bone mineral density were monitored before, during and up to 3 months after the course of GnRH agonist therapy. RESULTS: N-telopeptide levels increased significantly throughout GnRH agonist therapy and returned to baseline levels by 3 months after treatment was completed. A significant negative correlation was seen between N-telopeptide and E2 measurements after 3 months (r=-0.23, P<.05), 4 months (r=-0.32, P < .05), and 5 months (r=-0.41, P<.005) of GnRH agonist therapy. The percent change in bone mineral density at L1-L4 at 6 months of GnRH agonist treatment correlated inversely with the percent change in N-telopeptides from baseline to 2,3,4, and 5 months of treatment; the percent change of bone mineral density at the femoral neck at 6 months correlated inversely with the percent change of N-telopeptides from baseline to month 4. CONCLUSIONS: Urinary N-telopeptide determinations provide a quantitative measure of bone resorption, due to GnRH agonist-induced hypoestrogenism. Increases in resorption as measured by N-telopeptides parallel decreases in in E2 levels. Increases in N-telopeptides on GnRH agonist therapy may provide a tool to predict decreases in bone mineral density.

Cost comparisons between nafarelin and leuprolide in the treatment of endometriosis.

The objective of this study was to compare the cost and effectiveness of nafarelin versus leuprolide in the treatment of endometriosis. To compare the economic impact of treating endometriosis with leuprolide or nafarelin and to facilitate cost comparisons between the two, we statistically analyzed information concerning the costs of medications for the treatment of endometriosis, outpatient services, and management of adverse effects, as well as other related costs. A national claims database, MarketScan, was used to obtain data on patients with a principal diagnosis of endometriosis who were treated with either leuprolide or nafarelin. During the calendar years 1992-1994, 114 patients with endometriosis had claims for nafarelin, and 343 had claims for leuprolide. There were no significant differences between nafarelin and leuprolide recipients with respect to demographic variables, types of concomitant drug used, types of outpatient service received, or major outpatient diagnostic categorization. In 1994 dollars, the cost of using leuprolide was $326.7 greater than that of using nafarelin. The results of this study suggest that nafarelin is a less expensive alternative to leuprolide for the treatment of endometriosis.

Gonadotropin-releasing hormone analogues for the treatment of endometriosis: long-term follow-up.

OBJECTIVE: To determine the long-term recurrence rate of endometriosis after treatment with gonadotropin-releasing hormone analogues (GnRH-a). DESIGN: A historical prospective study. SETTING: Royal Free Hospital, London, a tertiary referral center for the treatment of endometriosis. PATIENTS: One hundred thirty patients with endometriosis had treatment with GnRH-a buserelin acetate, goserelin, and nafarelin acetate between the years 1985 and 1987. Patients no longer being followed in the gynecology clinic were sent a questionnaire to determine their state of health. Information was also requested from the patient's general practitioner. MAIN OUTCOME MEASURES: The cumulative recurrence rate for the fifth year after treatment ended was 53.4%. RESULTS: Patients with a higher disease stage at the outset were more likely to experience recurrence and experience it earlier than patients with minimal disease. Fifth-year recurrence rates were 36.9% for minimal disease and 74.4% for severe disease. The change in endometriosis stage classification scores at second-look laparoscopy for those patients whose disease recurred after treatment was not significantly different from those whose disease did not recur during the study period. CONCLUSIONS: Patients with endometriosis treated with GnRH-a are highly likely to suffer a recurrence of their disease, particularly if their disease is severe at the outset.

Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis.

OBJECTIVE: To evaluate the efficacy of the GnRH agonist (GnRH-a) nafarelin compared with placebo administered for 6 months after reductive laparoscopic surgery for symptomatic endometriosis. DESIGN: Randomized, prospective, placebo-controlled, multicenter clinical trial. SETTING: Thirteen clinics including private practice and university centers. PATIENT(S): One hundred nine women aged 18-47 with laparoscopically proven endometriosis and pelvic pain who had undergone reductive laparoscopic surgery for endometriosis. INTERVENTION(S): Patients were randomized to receive either the GnRH-a nafarelin (200 micrograms twice daily) or placebo for 6 months. MAIN OUTCOME MEASURE(S): Time to initiation of alternative treatment (the length of time from beginning study medication to receiving alternative therapy or to deeming that the study drug was ineffective) and patient-reported and physician-assessed pelvic pain scores. RESULT(S): The median time to initiation of alternative treatment was > 24 months in the nafarelin group versus 11.7 months in the placebo group. Fifteen (31%) of 49 nafarelin-treated patients required alternative therapy, compared with 25 (57%) of 44 placebo-treated patients. The patients' pelvic pain scores dropped significantly in the nafarelin and placebo groups after 6 months of treatment. Physician summary ratings showed significant improvement in the nafarelin group and no significant changes in the placebo group after 6 months of treatment. CONCLUSION(S): Compared with placebo, nafarelin administered after reductive laparoscopic surgery for endometriosis significantly delays the return of endometriosis symptoms requiring further treatment.

Memory complaints associated with the use of gonadotropin-releasing hormone agonists: a preliminary study.

OBJECTIVES: To study the effect of GnRH agonist (GnRH-a) treatment on memory and to assess the role of psychological factors. DESIGN: A randomized prospective study. SETTING: An academic teaching hospital. PARTICIPANTS: Women with endometriosis and infertility or endometriosis alone. MAIN OUTCOME MEASURES: Memory Observation Questionnaire, Profile of Mood States, Health Concerns scale, a weekly diary of adverse effects. RESULTS: Perceived memory functioning decreased during GnRH-a administration and by the final week of treatment 44% of women reported moderate to marked impairment in comparison to community norms. Prospective memory was most affected and withdrawal of GnRH-a treatment resulted in a return to normal memory functioning. Impairment was not related to excessive health concerns or mood changes and was uncorrelated with other adverse effects. CONCLUSIONS: Memory disruption may be a more common side effect of GnRH-a treatment than currently is recognized. Problems were temporary and more likely a result of rapid estrogen depletion than a consequence of mood, somatic distress, or personality factors.