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 case of progesterone-induced anaphylaxis, cyclic urticaria/angioedema, and autoimmune dermatitis.

OBJECTIVE: Women have exhibited anaphylaxis, urticaria/angioedema, and autoimmune progesterone dermatitis (APD) coinciding with the progesterone premenstrual rise. We report a detailed immunological evaluation of such a woman responsive to a gonadotropin hormone-releasing agonist (GHRA). METHODS: Skin testing, enzyme-linked immunosorbent assays (ELISAs), leukocyte histamine release (LHR), and inhibition assays were performed to demonstrate progesterone immunoresponsiveness. RESULTS: Serum specific-progesterone immunoglobulin G (IgG) and IgE were detected initially and disappeared 6 months after GHRA treatment. Dose-response LHR using patient basophils was observed for different hormones but after 3 months persisted only for 5ß-pregnanediol. Preincubation with mouse antiprogesterone monoclonal antibody (PmAb) or mifepristone, a progesterone inhibitor, over a range of doses inhibited specific progesterone-induced LHR. Experiments with varying progesterone concentrations and a fixed dose of anti-IgE resulted in 100% LHR at a concentration as low as 0.016 nmol/mL, which, without anti-IgE, failed to release histamine. CONCLUSIONS: This is the first report of combined recurrent anaphylaxis, cyclic urticaria/angioedema, and APD induced by immunoresponsiveness to progesterone.

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.

Sterile abscess formation in response to two separate branded long-acting gonadotropin-releasing hormone agonists.

BACKGROUND: Long-acting forms of gonadotropin-releasing hormone (GnRH) receptor agonists are commonly used for the treatment of central precocious puberty (CPP). Sterile abscess formation has been reported as a complication of leuprolide acetate, but not histrelin acetate. OBJECTIVE: The aim of this study was to report an adverse drug reaction in a child with sterile abscess formation following treatment with 2 different branded long-acting forms of GnRH agonists. CASE SUMMARY: An otherwise healthy 8-year-old white female (weight, 40.7 kg; height, 140.1 cm) with documented CPP and no known drug allergies developed a sterile abscess at the site of the monthly intramuscular injection of 15 mg of leuprolide acetate. Because of this site reaction, a 50-mg histrelin acetate insert was placed in the patient's left arm. A similar reaction occurred 2 weeks after insert placement on 2 separate occasions in different arms. At the time of the removal of the second insert, Gram stain and swab culture of the purulent wound discharge were negative. The child was subsequently treated with intranasal nafarelin (800 ug twice daily) and tolerated it well. The Naranjo Adverse Drug Reaction Causality Score was 10 (definite, ≥9). CONCLUSION: This report describes a case of sterile abscess formation definitely associated with 2 different forms of long-acting GnRH agonist treatment in a child.

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.

Teriparatide (recombinant human parathyroid hormone 1-34) in postmenopausal women with osteoporosis: systematic review.

CONTEXT AND OBJECTIVE: Osteoporosis is defined as a disease characterized by low bone mass and deterioration of the bone tissue microarchitecture. Teriparatide stimulates the formation and action of osteoblasts, which are responsible for bone formation, thus promoting bone tissue increase. The aim was to assess the effectiveness and safety of teriparatide for treating postmenopausal osteoporosis. METHODS: A systematic review was conducted using the Cochrane Collaboration methodology. RESULTS: 1) Teriparatide 20 microg or 40 microg versus placebo: there was a benefit from teriparatide, considering the following outcomes: reduction in the number of new vertebral and non-vertebral fractures, and increased whole-body, lumbar and femoral bone mineral density. 2) Teriparatide 40 microg versus alendronate 10 mg/day for 14 months: there was no statistical difference regarding the incidence of new vertebral or non-vertebral fractures, although in the group that received teriparatide there was greater bone mineral density increase in the whole body, lumbar column and femur. 3) Estrogen plus teriparatide 25 microg versus estrogen: there was a benefit, considering the following outcomes: reduction in the number of new vertebral fractures, and increased whole-body, lumbar and femoral bone mineral density after three years. CONCLUSIONS: When teriparatide is intermittently administered in low doses, it reduces the incidence of vertebral fractures (67%) and non-vertebral fractures (38%) and increases bone mineral density in the lumbar column and femur. There is a need for studies with longer observation in order to allow conclusions regarding the safety and duration of the therapeutic effects.

Teriparatide (recombinant human parathyroid hormone 1-34) in postmenopausal women with osteoporosis: systematic review / Teriparatida (hormônio recombinante humano da paratireóide 1-34) para mulheres com osteoporose pós-menopausa: revisão sistemática

CONTEXT AND OBJECTIVE: Osteoporosis is defined as a disease characterized by low bone mass and deterioration of the bone tissue microarchitecture. Teriparatide stimulates the formation and action of osteoblasts, which are responsible for bone formation, thus promoting bone tissue increase. The aim was to assess the effectiveness and safety of teriparatide for treating postmenopausal osteoporosis. METHODS: A systematic review was conducted using the Cochrane Collaboration methodology. RESULTS: 1) Teriparatide 20 µg or 40 µg versus placebo: there was a benefit from teriparatide, considering the following outcomes: reduction in the number of new vertebral and non-vertebral fractures, and increased whole-body, lumbar and femoral bone mineral density. 2) Teriparatide 40 µg versus alendronate 10 mg/day for 14 months: there was no statistical difference regarding the incidence of new vertebral or non-vertebral fractures, although in the group that received teriparatide there was greater bone mineral density increase in the whole body, lumbar column and femur. 3) Estrogen plus teriparatide 25 µg versus estrogen: there was a benefit, considering the following outcomes: reduction in the number of new vertebral fractures, and increased whole-body, lumbar and femoral bone mineral density after three years. CONCLUSIONS: When teriparatide is intermittently administered in low doses, it reduces the incidence of vertebral fractures (67 percent) and non-vertebral fractures (38 percent) and increases bone mineral density in the lumbar column and femur. There is a need for studies with longer observation in order to allow conclusions regarding the safety and duration of the therapeutic effects.

CONTEXTO E OBJETIVO: A osteoporose é definida como uma doença caracterizada por baixa massa óssea e deteriorização da microarquiquetura do tecido ósseo. O paratormônio estimula a formação e a ação dos osteoblastos responsáveis pela formação dos ossos, promovendo ganho de tecido ósseo. O objetivo foi determinar a efetividade e a segurança da teriparatida no tratamento da osteoporose pós-menopausa. MÉTODOS: Foi realizada uma revisão sistemática da literatura de acordo com a metodologia da Colaboração Cochrane. RESULTADOS: 1) Teriparatida 20 µg ou 40 µg versus placebo: benefício da teriparatida considerando os desfechos redução do número de novas fraturas vertebrais e não-vertebrais, aumento da densidade mineral óssea corporal total, lombar e do fêmur. 2) Teriparatida 40 µg versus alendronato 10 mg/dia por 14 meses: não houve diferença estatística em relação a incidência de novas fraturas vertebrais ou não-vertebrais, porém, no grupo que recebeu a teriparatida, houve maior ganho de densidade mineral óssea corporal total, na coluna lombar e no fêmur (região intertrocantérica e triângulo de Wards). 3) Estrogênio mais teriparatida 25 µg versus estrogênio: houve benefício do estrogênio associado a teriparatida considerando os desfechos redução do número de novas fraturas vertebrais, aumento da densidade mineral óssea corporal total, lombar e do fêmur ao final dos três anos do estudo. CONCLUSÕES: A teriparatida, quando administrada em baixas doses e de forma intermitente, reduz as fraturas vertebrais (67 por cento) e não vertebrais (38 por cento) e aumenta a densidade mineral óssea na coluna lombar e no fêmur. Há necessidade de estudos de maior tempo de observação para permitir conclusões sobre a segurança e a duração dos efeitos terapêuticos.

GnRH analogs: options for endometriosis-associated pain treatment.

While none of the currently available treatment options for endometriosis pain resolved the underlying disease process, there are growing numbers of medical alternatives available. Medical options include the GnRH agonists and antagonists. Review of these treatments in the management of endometriosis pain and the insight often to the etiology of endometriosis are presented for discussion.

A relative reduction in mid-follicular LH concentrations during GnRH agonist IVF/ICSI cycles leads to lower live birth rates.

BACKGROUND: The effect of early- and mid-follicular LH concentrations on the ovarian response and pregnancy outcomes was evaluated in women receiving pituitary down-regulation with a GnRH agonist and ovarian stimulation with recombinant FSH (rFSH) during IVF/ICSI treatment. METHODS: Blood samples were collected prospectively from 701 cycles (560 patients) of assisted reproduction and analysed retrospectively. On the basis of LH concentrations on stimulation day 7/8, the patients were divided into two groups: LH<1.2 IU/l (n=179) and LH>or=1.2 IU/l (n=522). Cycle outcomes were also compared on the basis of a ratio of mid- to early-follicular LH concentrations (0.5, n=491). RESULTS: Patients with low LH concentrations were found to have a significant reduction in the late-follicular estradiol concentrations (P<0.001), the number of oocytes retrieved (P<0.01) and the number of usable embryos (P<0.01), and they required significantly more rFSH (430 IU difference, P<0.01). These differences did not translate into a significant change in live birth rates. Conversely, a ratio of or=50%) was associated with a significant reduction in live birth rates per embryo transfer and per cycle started (27.3 versus 19.0%, P<0.05 and 22.2 versus 15.8%, P<0.05, respectively). CONCLUSIONS: Low mid-follicular levels of LH have a significant impact on ovarian response but not on live birth rates. A fall in LH level of >or=50% from the early- to mid-follicular phase resulted in a lower live birth rate.

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.

Serum levels of prostate-specific antigen and androgens after nasal administration of a gonadotropin releasing hormone-agonist in hirsute women.

We aimed to determine whether ovarian suppression affects the production rate of prostate-specific antigen (PSA) in hirsute women. A total of 34 hirsute women who had a modified Ferriman-Gallwey (FG) score of > or = 7 and 14, non-hirsute women as the control group were recruited for this prospective controlled study. Serum samples for evaluation of basal hormones and PSA concentration were collected and were analyzed by commercial kits and chemiluminescent enzyme immunoassay. The hirsute women were given 400 microg/day nafarelin acetate for 3 months. Basal hormones, PSA levels and FG scores were then assessed. ANOVA and Tukey test were used to compare differences in means between the hirsute and the non-hirsute group at the beginning of the study. Student's t test, Tukey test and repeated measures variance analysis were used to evaluate differences in the study group and between the women with polycystic ovary syndrome (PCOS) and idiopathic hirsutism after gonadotropin releasing hormone (GnRH)-agonist administration. Statistical significance was assumed with a value of p < 0.05. PCOS and idiopathic hirsutism were diagnosed in 58.8% and 41.2% of 34 hirsute women, respectively. Age and body mass index (BMI) were similar in the hirsute and the control group (p > 0.05). FG scores in the PCOS group (20.3 +/- 1.7) were statistically similar to those of the group with idiopathic hirsutism (17.6 +/- 1.7) (p > 0.05). The non-hirsute women had significantly lower serum PSA concentrations than the hirsute group (p < 0.001). The basal mean level of PSA was 0.095 +/- 0.001 in the PCOS, 0.0061 +/- 0.009 in the idiopathic hirsute and 0.0040 +/- 0.004 ng/ml in the control group. No significant difference in the mean PSA levels was noted between the PCOS and the idiopathic hirsute subgroups before and after GnRH agonist treatment (0.0096 +/- 0.01 and 0.0051 +/- 0.032 ng/ml, respectively) (p > 0.05). FG scores, testosterone, 17alpha-hydroxyprogesterone and dehydroepiandrosterone sulfate levels were significantly decreased in the hirsute group following treatment (p < 0.001). PSA levels in hirsute women were higher than in non-hirsute women and independent of BMI, age and androgen deprivation. PSA concentration may be mediated through extragonadal sites and possibly through a long-standing hyperandrogenemic environment such as in PCOS and idiopathic hirsutism. Further investigation as to the significance of PSA in women with hirsutism and whether antiandrogens directly act to inhibit biosynthesis of PSA is warranted.

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.