Suboptimal response to GnRH-agonist trigger during oocyte cryopreservation: a case series.

BACKGROUND: Random-start, controlled ovarian stimulation (COS) has advanced the field of fertility preservation, allowing patients to expedite fertility treatment and avoid further delays to their cancer therapy. This novel approach allows patients to initiate ovarian stimulation at any point, regardless of where they are in their menstrual cycle. Luteal-phase start (LPS) protocols describe treatment cycles where COS is initiated during the luteal-phase of the menstrual cycle. LPS protocols have not been studied or optimized to the same degree as conventional, early-follicular COS. Particularly, there is a paucity of evidence evaluating treatment outcomes using different trigger medications in LPS protocols. The present study aims to evaluate the efficacy of using a GnRH agonist (GnRH-a) trigger in patients undergoing oocyte cryopreservation in LPS protocols. METHODS: This descriptive case series describes two patients, recently diagnosed with cancer, who underwent oocyte cryopreservation using an LPS protocol and a GnRH-a trigger at a university-affiliated, academic center. RESULTS: The patients described in our case series both failed to adequately respond to a GnRH-a trigger, based on their serum levels of luteinizing hormone (LH) and progesterone 12 h after their GnRH-a trigger. They both required a single rescue dose of human chorionic gonadotropin (hCG). CONCLUSIONS: These findings highlight the potential risk of a suboptimal response to a GnRH-a trigger in patients undergoing LPS, controlled ovarian stimulation for oocyte cryopreservation. This risk might be attributed to the downregulation of GnRH receptors by elevated serum progesterone levels during the luteal phase. Currently, there is insufficient evidence to recommend for or against the use of a GnRH-a trigger during LPS controlled ovarian stimulation. This case series offers a number of management strategies to mitigate this risk and emphasizes the need for further research in this area.

DuoStim: a new option for fertility preservation for a woman with Turner syndrome.

INTRODUCTION: Turner syndrome (TS) is associated with hypergonadotropic hypogonadism due to gonadal dysgenesis, which results in premature ovarian failure and subsequent infertility. Therefore, counseling and evaluation for fertility preservation are required as early as possible for women with TS. CASE PRESENTATION: A 23-year-old unmarried woman with mosaic TS (45, X [4/30] 46, XX [26/30]) presented to the pediatric department of our hospital for fertility counseling; she was accompanied by her mother. She was referred to the reproduction center of our hospital for ovarian reserve assessment and counseling regarding fertility preservation. We decided to retrieve oocytes using DuoStim as the controlled ovarian stimulation protocol. During the first and second oocyte retrievals, a total of 17 (9 and 8, respectively) mature metaphase II oocytes were cryopreserved. CONCLUSION: DuoStim may be a useful option for fertility preservation for women with TS and reduced ovarian reserve. This new strategy may obtain the required number of oocytes in the shortest time and preserve the future fertility of women with TS.

Current Medical Strategies in the Prevention of Ovarian Hyperstimulation Syndrome

The purpose of this review is to analyze current medical strategies in the prevention of ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation for in vitro fertilization. Owing to contemporary preventive measures of OHSS, the incidence of moderate and severe forms of the syndrome varies between 0.18% and 1.40%. Although none of medical strategies is completely effective, there is high-quality evidence that replacing human chorionic gonadotropin (hCG) by gonadotropin-releasing hormone (GnRH) agonists after GnRH antagonists and moderate- quality evidence that GnRH antagonist protocols, dopamine agonists and mild protocols reduce the occurrence of OHSS. Among various GnRH agonists, buserelin 0.5 mg, triptorelin 0.2 mg and leuprolide acetate (0.5-4 mg) have been mostly utilized. Although GnRH trigger is currently regarded as the best tool for OHSS prevention, intensive luteal support with exogenous administration of estradiol and progesterone or low-dose hCG on the day of oocyte retrieval or on the day of GnRH agonist trigger are required to achieve optimal conception rates due to early luteolysis. Among currently available dopamine agonists, cabergoline, quinagolide and bromocriptine are the most common drugs that should be used for prevention of both early and late OHSS. Mild stimulation protocols offer attractive option in OHSS prevention with satisfactory pregnancy rates.

Addition of low-dose hCG to rFSH during ovarian stimulation for IVF/ICSI: is it beneficial?

PURPOSE: The aim of the study was to assess the eftect ot the addition or iow-cose numan cnononic gonauoiropm (hCG) to ovarian stimulation with recombinant follicle stimulating hormone (rFSH) on in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcome. MATERIALS AND METHODS: This retrospective clinical study was conducted on 141 women undergoing ICSI through a short GnRH-agonist protocol with rFSH and the addition of low-dose (100 IU/day) hCG. The control group consisted of 124 women undergoing ovarian stimulation with a similar protocol devoid of hCG. Statistical analysis in the study population along with a subgroup analysis for age 35 years and 36 years was performed. RESULTS: Women in hCG group were statistically significant older and with higher basal FSH compared to control group. This can be attributed to the Centre's latent tendency to add hCG in the stimulation protocol in poor prognosis patients. Despite this fact and the fact that several ovarian stimulation parameters, such as peak estradiol levels, number of oocytes retrieved, number of mature oocytes, and fertilization rates were in favor of the control group, the quality of transferred embryos and pregnancy rates were in favor of hCG group. Similar results were obtained in the subgroup analyses apart from peak estradiol levels, which did not differ among the study groups. CONCLUSIONS: The addition of hCG to rFSH may be associated with better quality embryos and higher pregnancy rates, even in women of advanced reproductive age with higher basal FSH levels, which are often considered to have poorer ovarian reserve.

Ovarian hyperstimulation syndrome: a clinical report on 4894 consecutive ART treatment cycles.

BACKGROUND: Although a large number of studies have been dedicated to ovarian hyperstimulation syndrome (OHSS) none gave full embryological and clinical outcomes comparing oocyte trigger with human chorionic gonadotrophin (HCG) versus with a gonadotrophin-releasing hormone (GnRH) agonist (Buserelin) in cases with suspicious OHSS. The aim of the present study was thus to analyze 4894 consecutive assisted reproductive treatment cycles to undercover associated risk factors for development of OHSS, and the effects of the use of Buserelin as ovulation trigger on embryological and clinical outcomes. METHODS: In the 51 cases that developed OHSS, ovulation trigger was performed with HCG as indicators were not suspicious for OHSS. These were compared against two types of groups: 71 cases where Buserelin was used for ovulation induction due to suspicious development of OHSS; and those remaining 4772 cases where ovulation trigger was currently performed with HCG (control). RESULTS: Of the cases treated with Buserelin the oocyte maturation rate and the ongoing pregnancy rate were significantly lower, with higher rates of ectopic pregnancy and newborn malformations, but none developed OHSS. Of the OHSS cases, 23 needed hospitalization, with no major complications. CONCLUSIONS: Young age, lower time of infertility, lower basal follicle stimulating hormone levels, higher number of cases with female factor and polycystic ovarian syndrome, high number of follicles and higher estradiol concentrations were the risk factors found associated with OHSS. Cases with OHSS also presented higher follicle count but the estradiol levels were within the normal range. It thus remains to develop more strict criteria to avoid all cases with OHSS.

Retrospective comparison of GnRH agonist trigger with HCG trigger in GnRH antagonist cycles in anticipated high-responders.

All IVF-ICSI cycles carried out between October 2009 and October 2012 using GnRH agonist (GnRHa) ovulation trigger (n = 62) followed by a single dose of HCG plus progesterone and oestradiol in the luteal phase because of anticipated ovarian hypertsimulation were retrospectively compared with historic control cycles using HCG trigger (n = 29) and standard luteal phase support. Women's mean age, body mass index, anti-Müllerian hormone, FSH, LH, starting and total stimulation dose, number of follicles, oocytes, embryos, fertilization, implantation, polycystic ovary syndrome, ICSI, live birth and ongoing pregnancy rates per embryo transfer were similar (GnRHa 40.7% versus HCG 35.0%). For each started cycle, GnRHa resulted in 11.4% higher (statistically non-significant) live birth and ongoing pregnancy rate (OR 1.73, CI 0.64 to 4.69), with a similar difference for double-embryo transfers (OR 1.62, CI 0.44 to 6.38) and less need for freezing all embryos (9.7% versus 27.6%; P = 0.04). Incidence of mild-to-moderate OHSS was 16.2% with GnRHa trigger and 31.0% with HCG trigger) and no severe OHSS in the former. The addition of single low-dose HCG in the luteal phase after GnRHa trigger for suspected high-responders reduced the incidence of OHSS with good clinical outcomes, compared with HCG trigger.

Cardiovascular adverse events-related to GnRH agonists and GnRH antagonists: analysis of real-life data from Eudra-Vigilance and Food and Drug Administration databases entries.

INTRODUCTION AND OBJECTIVES: GnRH agonists and GnRH antagonists are two of the mainstays of hormonal therapy (HT) for prostate cancer (PCa). These drugs are at increased risk of cardiovascular (CV) adverse events (AEs). Aim of our study was to compare real-life data on AEs associated with GnRH agonists and GnRH antagonists based on Eudra-Vigilance (EV) and Food and Drug Administration (FDA) reported AEs. MATERIALS AND METHODS: EV and FDA databases were queried and the number of CV adverse events (AEs) for degarelix, buserelin, goserelin, leuprorelin, triptorelin until September 2021 were recorded. Specific CV AEs were recorded and data were analyzed per age and severity. pooled relative risk (PRR) was used to compare data between drugs. RESULTS: CV events were reported in 315/5128 (6%) for Degarelix, in 55/628 for Buserelin (9%), in 843/12,145 (7%) for Goserelin, in 3395/71,160 (5%) for Leuprorelin and in 214/4969 (5%) for Triptorelin. In terms of specific CV disorders, Degarelix presented lower risk of hypertension (PRR 0.60 (95% CI 0.37-0.98), p = 0.04), of myocardial infarction (PRR 0.05 (95% CI 0.01-0.39), p < 0.01) and thrombosis (PRR 0.14 (0.02-1.07), p = 0.06) when compared to GnRH agonists. Overall, younger patients (<65 years) presented a very low risk of CV AEs. Side effects were classified as serious in 90-96% of the cases. Fatal AEs were 5-20% over the CV AEs and 0.2-1% over the total AEs. CONCLUSIONS: Real-life data are consistent with registry studies regarding side effects related to HT. Real-life data suggest GnRH agonists are associated with higher CV AEs when compared to GnRH antagonists. Clinicians should consider these data when prescribing HT especially in patients with CV comorbidities.

The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives.

In stimulated IVF/intracytoplasmic sperm injection cycles, the luteal phase is disrupted, necessitating luteal-phase supplementation. The most plausible reason behind this is the ovarian multifollicular development obtained after ovarian stimulation, resulting in supraphysiological steroid concentrations and consecutive inhibition of LH secretion by the pituitary via negative feedback at the level of the hypothalamic-pituitary axis. With the introduction of the gonadotrophin-releasing hormone-(GnRH) antagonist, an alternative to human chorionic gonadotrophin triggering of final oocyte maturation is the use of GnRH agonist (GnRHa) which reduces or even prevents ovarian hyperstimulation syndrome (OHSS). Interestingly, the current regimens of luteal support after HCG triggering are not sufficient to secure the early implanting embryo after GnRHa triggering. This review discusses the luteal-phase insufficiency seen after GnRHa triggering and the various trials that have been performed to assess the most optimal luteal support in relation to GnRHa triggering. Although more research is needed, GnRHa triggering is now an alternative to HCG triggering, combining a significant reduction in OHSS with high ongoing pregnancy rates.

An investigational ovarian stimulation protocol increased significantly the psychological burden in women with premature ovarian failure.

OBJECTIVE: To assess the psychological impact (Hospital Anxiety and Depression Scale) of an investigational ovarian stimulation protocol in women with premature ovarian failure (POF). DESIGN: Prospective longitudinal study. POPULATION: Ten women with POF. METHODS: Women with idiopathic POF were placed on three consecutive treatment cycles consisting of gonadotropin ovarian stimulation after estrogen priming, gonadotropin-releasing hormone agonist pituitary desensitization, and corticosteroid immune suppression. RESULTS: Median anxiety and depression scores increased significantly from baseline following three consecutive treatment cycles from 4.0 (range 2.0-8.0) to 11.0 (range 10.0-14.0) (p-value 0.041) and from 1.5 (range 0-6.0) to 9.0 (range 7.0-10.0) (p-value 0.039), respectively. There were nine "probable" anxiety (90%) and three "probable" depression (30%) cases on the final treatment cycle compared with none (0%) on baseline (p-value 0.004 and 0.250, respectively). CONCLUSIONS: The use of investigational ovarian stimulation protocols in women with idiopathic POF was associated with excessive psychological strain. Women with POF should be cautioned against the potentially harmful aspect of similar treatments of unproven benefit.

Treatment of endometriosis in different ethnic populations: a meta-analysis of two clinical trials.

Approaches to the treatment of endometriosis vary worldwide, but studies comparing endometriosis medications in different ethnic groups are rare. A systematic literature search identified two studies directly comparing dienogest (DNG) versus gonadotropin-releasing hormone (GnRH) analogues in European and Japanese populations. Meta-analysis of visual analogue scale scores revealed no heterogeneity in response between the trials, indicating equivalent efficacy of DNG and GnRH analogues for endometriosis-related pain across populations. DNG was significantly superior to GnRH analogues for bone mineral density change in both trials, but significant heterogeneity between the studies may indicate ethnic differences in physiology.

Autoimmune progesterone dermatitis: a diagnosis easily missed.

Autoimmune progesterone dermatitis (AIPD) is a rare, poorly characterized dermatosis, with about 60 previously reported cases. It typically undergoes cyclical flares relating to the menstrual cycle, especially the luteal phase, when levels of progesterone are at their highest. We report the case of a 34-year-old woman with an 8-year history of a profoundly pruritic eruption, associated with her menstrual cycle, in whom the diagnosis had proved elusive. Buserelin nasal spray resulted in complete clearance. AIPD is a diagnosis to consider in intractable eruptions in women, particularly if there is cyclical variation.

IVM is an alternative for patients with PCO after failed conventional IVF attempt.

PURPOSE: To determine if IVM of oocytes from unstimulated cycle is a treatment option for patients who did not deliver after standard IVF-ET. METHOD: Twenty three women with PCO, thirteen of them with normal cycles and all <35 years old, who failed IVF served as their own control. During the control IVF cycle patients were stimulated with 1730.7 ± 639.5 IU recombinant FSH, a long Buserelin acetate protocol was used and embryo transfer was performed on day 2 or 3 after ICSI. After failed IVF immature oocytes were aspirated transvaginally from antral follicles during spontaneous menstrual cycle. Embryo transfer was performed 2 or 3 days later. RESULT: 11.4 ± 4.8 mature oocytes and 6.7 ± 3.2 embryos were produced with IVF, which served as the control, compared to 9.7 ± 4.5 mature oocytes and 6.2 ± 3.2 embryos with IVM. There was one clinical pregnancy in the IVF group which did not result in a live birth where as five singleton and one pair of twins with healthy live births and one miscarriage in the IVM group. CONCLUSION: IVM does not involve ovarian stimulation with possible financial and health consequences. It may be an useful treatment after unsuccessful IVF.

Outcome of pregnancies after inadvertent exposure to GnRH agonist in early pregnancy.

Four pregnancies were exposed to gonadotrophin-releasing hormone agonist (GnRHa) during early pregnancy and the patients were followed up to find out the outcome of their pregnancies. In three patients long-acting GnRHa (triptorelin acetate 3.75 mg) once monthly was used for severe pelvic endometriosis as part of preparation for undergoing assisted reproductive technology (ART) cycle, and in one patient daily injections of short-acting GnRHa (buserelin 0.05 mg) was given for down-regulation for ART cycle. The age of the patients ranged from 29 to 38 years and duration of infertility was 3 to 13 years. In patients prescribed long-acting GnRHa, diagnosis of pregnancy was done late at around 5-8 weeks by ultrasonography, whereas in patients using short-acting GnRHa diagnosis of pregnancy was made with blood beta human chorionic gonadotropin (HCG) level after the 26th day of injections. Three pregnancies were delivered around term and the babies had no apparent complication or any congenital anomaly. One of the pregnancies ended up into spontaneous abortion at 14 weeks of pregnancy. The children were regularly examined by pediatricians regarding physical and mental development and for any abnormal behavioral problems. All of them are normal till now.

Large prospective, pregnancy and infant follow-up trial assures the health of 1000 fetuses conceived after treatment with the GnRH antagonist ganirelix during controlled ovarian stimulation.

BACKGROUND: A concern for new compounds in fertility treatment is the possible risk of perinatal complications or birth defects. To demonstrate long-term safety of ganirelix (GnRH antagonist) treatment in controlled ovarian stimulation (COS), follow-up data on pregnancy and neonatal outcome were analysed for 1000 fetuses (>or=16 gestational weeks). METHODS: Obstetrical and neonatal data on 839 pregnancies, resulting in 969 live born infants after ganirelix treatment were compared with a historical cohort of 753 pregnancies after long GnRH agonist (buserelin) treatment, resulting in 963 live born infants. All treatment cycles were performed in a single fertility centre. The infants were examined at the Universitair Ziekenhuis Brussel using an identical follow-up protocol. Incidence of major malformations (i.e. causing functional impairment or requiring surgical correction) was the primary end-point and was analysed by logistic regression including treatment, age of mother, IVF method and pregnancy type (singleton/multiple) as independent variables. RESULTS: There were no relevant differences in maternal characteristics, fertilization method and pregnancy and delivery complications between the ganirelix and historical GnRH agonist groups. There were relatively more multiple pregnancies in the historical GnRH agonist group (31.9%) than the ganirelix group (18.7%; P < 0.0001). The groups were comparable with respect to pregnancy loss after 16 weeks gestation. The incidence of major congenital malformations in fetuses with gestational age >or=26 weeks was 5.0% in the ganirelix cohort versus 5.4% in the historical GnRH agonist group (odds ratio 0.94, 95% confidence interval, 0.62-1.42). CONCLUSION: In terms of neonatal outcome and risk of major malformations, treatment with the GnRH antagonist ganirelix during COS is as safe as traditional GnRH agonists.

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.

Clinical outcome following stimulation with highly purified hMG or recombinant FSH in patients undergoing their first treatment cycle of IVF or ICSI.

OBJECTIVE: To test whether the clinical efficiency of recombinant FSH (rFSH) and highly purified human menotrophin (hMG) differs in terms of pregnancy and live birth rates during the first treatment cycle of IVF or ICSI. DESIGN: Prospective cohort study. SETTING: Department of Gynecology and Obstetrics, Rikshospitalet, Oslo University Hospital. STUDY POPULATION: Records of 1,136 infertile couples undergoing their first IVF (n = 682) or ICSI (n = 454) treatments were reviewed. The effect of hMG and rFSH was analyzed for the IVF and ICSI groups separately. METHODS: Patients received long term down-regulation with GnRH agonist and controlled ovarian hyperstimulation with hMG or rFSH. Oocytes were fertilized by IVF or ICSI. Embryos were transferred on Day 2. MAIN OUTCOME MEASURES: Primary outcome measures were pregnancy and live birth rates, secondary outcome measures were duration of treatment, doses of hMG or rFSH applied, number of oocytes retrieved and the number and quality of embryos obtained. RESULTS: Similar pregnancy and live birth rates were observed with hMG and rFSH. Compared to hMG, treatment cycles with rFSH were characterized by significantly shorter stimulation, lower gonadotrophin consumption, and increased number of oocytes and embryos. CONCLUSION: We conclude that rFSH and hMG are equivalent in terms of clinical efficacy.

Comparison of gonadotropin-releasing hormone agonists and antagonists in assisted reproduction cycles of polycystic ovarian syndrome patients.

AIM: Gonadotropin-releasing hormone (GnRH) antagonists have reduced the incidence of severe ovarian hyper stimulation syndrome (OHSS) and rate of hospitalization due to severe OHSS, especially in polycystic ovarian syndrome (PCOS) patients. The present study aimed to compare the outcomes of patients with PCOS undergoing controlled ovarian hyperstimulation (COH) with GnRH agonist versus GnRH antagonist protocols for assisted reproduction cycles. METHODS: The present clinical trial compared GnRH antagonist (cetrorelix) and GnRH agonist (buserelin) protocols during COH of 112 infertile PCOS patients entering assisted reproduction cycles. The primary outcome measure was pregnancy occurrence. Basal characteristics of the participants, stimulation cycle responses, pregnancy outcomes, incidence of OHSS and types of OHSS were considered in both groups. RESULTS: Regarding chemical and clinical pregnancy rates, the number of retrieved oocytes was significantly higher and OHSS was significantly lower in the antagonist group. Follicle stimulating hormone (FSH), luteinizing hormone (LH) levels, number of follicles, number of follicles >18 mm, relative frequency of mature oocytes, number and days of gonadotropin injections, day of human chorionic gonadotropin (HCG) administration, estradiol level and abortion were similar between the two groups. CONCLUSION: GnRH antagonists are more effective, safe and a well tolerated alternative to agonists for assisted reproduction cycles in PCOS patients. GnRH antagonists are associated with a reduction in the incidence of OHSS in these patients.

Scar endometriosis in the abdominal wall: a predictable condition for experienced surgeons.

PURPOSE: Endometriosis in surgical scars develops in 0.1% of those women who undergo Caesarean section or other obstetric surgery. Herein we analyse and discuss the clinico-pathological characteristics of 15 patients with scar endometriosis in the abdominal wall. METHODS: Fifteen cases of scar endometriosis in the abdominal wall that were treated surgically in our department between 2003 and 2009 were examined retrospectively. Age, parity, complaint, medical or surgical history, pre/postoperative hormonotherapy, size of the mass, surgical procedure, follow-up and disease recurrence were analysed. RESULTS: This retrospective study included 15 patients presenting with 17 postoperative abdominal wall masses. The mean age of the patients was 32.1 +/- 6.0 years (range, 23-48). Eleven of the patients had a painful mass that became bigger before menstruation, two had palpable masses only, and two were hospitalised because of a mass with persistent pain. The locations of the masses were as follows: eight were close to the right side and three were close to the left side; two were in the middle of the Pfanenstiel incision and two were in trocar tracts. The patients' surgical histories included Caesarean section in thirteen, bilateral laparoscopic ovarian cyst excision in one, and laparoscopic appendectomy in one. CONCLUSIONS: If a patient presents with incision pain and a palpable mass after gynaecologic surgery, an incisional endometrioma should be considered. Surgical excision and hormone therapy are effective treatment approaches in these patients.

Efficacy of long-term, low-dose gonadotropin-releasing hormone agonist therapy (draw-back therapy) for adenomyosis.

BACKGROUND: The usefulness of long-term, low-dose gonadotropin-releasing hormone agonist (GnRHa; buserelin acetate) therapy, so-called draw-back therapy, for the treatment of adenomyosis was investigated not. MATERIAL/METHODS: A retrospective observational study was conducted covering the period between January 2003 and March 2008. The subjects consisted of 12 patients with adenomyosis who underwent draw-back therapy for 2 years and had previously received GnRHa. GnRHa was initiated at 900 microg/day (6 nasal sprays/day). When the CA-125 level normalized, the GnRHa dosage was adjusted to 150-750 microg/day to achieve a plasma estradiol (E2) concentration of 20-50 pg/ml (i.e., the therapeutic window). Pain during withdrawal bleeding and chronic pelvic pain were assessed using a visual analogue scale. In addition, bone mineral density (BMD) of the lumbar vertebrae was measured using dual-energy X-ray absorptiometry. RESULTS: The mean GnRHa dose during draw-back therapy was 435 microg/day (2.9 nasal sprays/day). The mean E2 level during draw-back therapy was 36.3+/-14.3 pg/ml. The intensity of chronic pelvic pain was significantly lower during draw-back therapy than before draw-back therapy, and was nearly eliminated in many patients (4.8+/-1.2 vs. 0.6+/-0.7, respectively [p=0.000]). Compared to the severity of vasomotor symptoms during previous regular GnRHa therapy, the severity of vasomotor symptoms during draw-back therapy was significantly lower (3.8+/-0.7 vs 1.1+/-0.7, respectively [p=0.000]). The decrease in BMD during a 6-month course of treatment was 0.96+/-0.9%. CONCLUSIONS: GnRHa draw-back therapy allowed maintenance of plasma E2 levels within the therapeutic window. GnRHa can thus be administered for long periods of time while maintaining therapeutic effects on adenomyosis and suppressing adverse events.