1. Preimplantation genetic diagnosis does not increase pregnancy rates in patients at risk for aneuploidy.
   
2. A modified embryo cryopreservation method increases post-thaw survival with a concomitant increase in implantation
   

Gynaecologic Endocrinology

3. A randomized trial of superovulation with two different doses of letrozole.
   

Postmenopause/Osteology

4. Calcium plus vitamin D supplementation and the risk of fractures.
   
5. Denosumab in postmenopausal women with low bone mineral density.

1. Preimplantation genetic diagnosis does not increase pregnancy rates in patients at risk for aneuploidy.

A literature review and discussion of current evidence was undertaken to investigate the use of preimplantation genetic diagnosis (PGD) as a method for increasing pregnancy success rates in patients at high risk for aneuploidy. Preimplantation genetic diagnosis selects euploid embryos for transfer in assisted reproduction. Some investigators argue that it might be used to increase pregnancy rates in patient populations at high risk of aneuploidy, such as those with advanced maternal age (AMA), recurrent pregnancy loss (RPL), and recurrent IVF failure. Although analysis with PGD confirms a high rate of aneuploidy in patients with AMA, RPL, and recurrent IVF failure, its use in these patient populations has not been consistently shown, in the literature, to increase pregnancy rates. Randomized controlled trials with large patient populations, performed in programs with expertise in PGD technology, are needed before PGD can routinely be recommended as a means for increasing pregnancy rates in patients with AMA, RPL, and recurrent IVF failure.

Reference

Shahine LK, Cedars MI. Preimplantation genetic diagnosis does not increase pregnancy rates in patients at risk for aneuploidy. Fertil Steril. 2006 Jan;85(1):51-6.

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2. A modified embryo cryopreservation method increases post-thaw survival with a concomitant increase in implantation.

The modifications were made to achieve maximum post-thaw survival of frozen embryos. One hundred forty-five patients whose embryos were frozen and thawed according to the standard method, and 56 patients whose embryos were frozen and thawed according to a modified method. Modifications were made to the various steps of cryopreservation: freezing and thawing solutions, loading of embryos into the straws, and warming rates. With the modified method, 138 (93%) of the 149 embryos thawed for 56 patients survived freezing, and 79.8% had all their blastomeres intact, which is almost double the result obtained (41.8%) for patients whose embryos were thawed with the standard method. The implantation and pregnancy rates were also significantly higher with the modified method compared with the standard method.

Reference

Kattera S, Chen C. A modified embryo cryopreservation method increases post-thaw survival with a concomitant increase in implantation. Fertil Steril. 2005 Nov;84(5):1498-504.

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3. A randomized trial of superovulation with two different doses of letrozole.

The aim of this prospective randomized trial was to evaluate the effects of either a 2.5-mg or a 5-mg daily dose of letrozole in women undergoing superovulation and intrauterine insemination (IUI). The women were<40 years old, with patent fallopian tubes and infertility of >1 year in duration. Patients were randomized into either a 2.5-mg dose of letrozole (34 patients) or a 5-mg dose of letrozole (38 patients) daily for 5 days. When the leading follicle reached 18 mm in diameter, ovulation was triggered by an injection of hCG and IUI was performed 24 and 48 hours later. Compared with those treated with 2.5 mg of letrozole, the total number of follicles was significantly higher in patients receiving 5 mg of letrozole. No difference in the endometrial thickness was found between the two groups. The pregnancy rate per cycle in patients receiving 5mg of letrozole was statistically higher than in patients receiving 2.5 mg of letrozole (26.3% vs. 5.9%, P<.05). No multiple pregnancies occurred. Compared with the daily dose of 2.5 mg, 5 mg of letrozole is associated with more follicles and a higher pregnancy rate. It appears that 5 mg daily for 5 days is a preferable letrozole dose for superovulation.

Reference

Al-Fadhli R, Sylvestre C, Buckett W, Tan SL, Tulandi T. A randomized trial of superovulation with two different doses of letrozole. Fertil Steril. 2006 Jan;85(1):161-4

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4. Calcium plus vitamin D supplementation and the risk of fractures.

The efficacy of calcium with vitamin D supplementation for preventing hip and other fractures in healthy postmenopausal women remains equivocal. We recruited 36,282 postmenopausal women, 50 to 79 years of age, who were already enrolled in a Women's Health Initiative (WHI) clinical trial. We randomly assigned participants to receive 1000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Fractures were ascertained for an average follow-up period of 7.0 years. Bone density was measured at three WHI centers. Hip bone density was 1.06 percent higher in the calcium plus vitamin D group than in the placebo group (P<0.01). Intention-to-treat analysis indicated that participants receiving calcium plus vitamin D supplementation had a hazard ratio of 0.88 for hip fracture (95 percent confidence interval, 0.72 to 1.08), 0.90 for clinical spine fracture (0.74 to 1.10), and 0.96 for total fractures (0.91 to 1.02). The risk of renal calculi increased with calcium plus vitamin D (hazard ratio, 1.17; 95 percent confidence interval, 1.02 to 1.34). Censoring data from women when they ceased to adhere to the study medication reduced the hazard ratio for hip fracture to 0.71 (95 percent confidence interval, 0.52 to 0.97). Effects did not vary significantly according to prerandomization serum vitamin D levels. It is concluded that among healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density, did not significantly reduce hip fracture, and increased the risk of kidney stones.

Reference

Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, Bassford T, Beresford SA, Black HR, Blanchette P, Bonds DE, Brunner RL, Brzyski RG, Caan B, Cauley JA, Chlebowski RT, Cummings SR, Granek I, Hays J, Heiss G, Hendrix SL, Howard BV, Hsia J, Hubbell FA, Johnson KC, Judd H, Kotchen JM, Kuller LH, Langer RD, Lasser NL, Limacher MC, Ludlam S, Manson JE, Margolis KL, McGowan J, Ockene JK, O'Sullivan MJ, Phillips L, Prentice RL, Sarto GE, Stefanick ML, Van Horn L, Wactawski-Wende J, Whitlock E, Anderson GL, Assaf AR, Barad D; Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006 Feb 16;354(7):669-83.

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5. Denosumab in postmenopausal women with low bone mineral density.

Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162) binds RANKL with high affinity and specificity and inhibits RANKL action. The efficacy and safety of subcutaneously administered denosumab were evaluated over a period of 12 months in 412 postmenopausal women with low bone mineral density (T score of -1.8 to -4.0 at the lumbar spine or -1.8 to -3.5 at the proximal femur). Subjects were randomly assigned to receive denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open-label oral alendronate once weekly (at a dose of 70 mg), or placebo. The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase. Denosumab treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7 percent (as compared with an increase of 4.6 percent with alendronate and a loss of 0.8 percent with placebo), at the total hip of 1.9 to 3.6 percent (as compared with an increase of 2.1 percent with alendronate and a loss of 0.6 percent with placebo), and at the distal third of the radius of 0.4 to 1.3 percent (as compared with decreases of 0.5 percent with alendronate and 2.0 percent with placebo). Near-maximal reductions in mean levels of serum C-telopeptide from baseline were evident three days after the administration of denosumab. The duration of the suppression of bone turnover appeared to be dose-dependent. It is concluded that in postmenopausal women with low bone mass, denosumab increased bone mineral density and decreased bone resorption. These preliminary data suggest that denosumab might be an effective treatment for osteoporosis.

Reference

McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, Lain D, Kivitz AJ, Holloway DL, Zhang C, Peterson MC, Bekker PJ; AMG 162 Bone Loss Study Group. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006 Feb 23;354(8):821-31.

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