The role of LH in sensitizing antral follicles to FSH is unclear. LH is required for normal hormone production and normal oocyte and embryo development, but follicular responses to LH may depend upon the stage of development. Potential roles at the early follicular phase were explored in a clinical setting by employing a sequential approach to stimulation by recombinant human (r-h) LH followed by r-hFSH in women who were profoundly down-regulated by depo GnRH agonist.
We employed a multi-centre, prospective, randomized approach. Women (n = 146) were treated in a long course high-dose GnRH agonist (Decapeptyl, 4.2 mg s.c.) protocol and were randomized to receive r-hLH (Luveris, 300 IU/day) for a fixed 7 days, or no r-hLH treatment. This was followed by a standard r-hFSH stimulation regime (Gonal-F, 150 IU/day). Ultrasound and hormone assessments of responses were measured at the start of r-hLH treatment, on FSH stimulation Days 0 and 8 and at the time of HCG administration.
The LH treatment was associated with increased small antral follicles prior to FSH stimulation (P = 0.007), and an increased yield of normally fertilized (2 PN) embryos (P = 0.03). There was no influence of the r-hLH pretreatment upon hormone profiles or ultrasound assessments during the FSH phase. Anti-mullerian hormone increased in both groups during the week prior to FSH stimulation (P = 0.002).
This sequential approach to the use of r-hLH in standard IVF showed a possible modest clinical benefit. The results support other recent work exploring up-regulated androgen drive upon follicular metabolism indicating that clinical benefit may be obtainable after further practical explorations of the concept.
"Two approaches have so far been explored: one to promote theca-cell activity (with LH or HCG administration) and the other to increase intrafollicular androgen concentrations before FSHmediated recruitment (using aromatase inhibitors). The first strategy was investigated in a study of down-regulated IVF patients randomized to either 1 week's pretreatment with recombinant LH or to continuing down-regulation prior to ovarian stimulation (no pretreatment) (Durnerin et al., 2008). While results showed no indication of any quantitative effect of the LH pretreatment in terms of follicular sensitivity to FSH or ovarian hormone secretions, there was a non-significant increase in oocyte yield and a significant increase in normal embryo yield (from an average of 5.1 to 7.0 per patient). "
[Show abstract][Hide abstract] ABSTRACT: The prediction of extremes of ovarian response to stimulation and the irreversibility of reduced ovarian reserve remain important clinical and basic science research issues of IVF treatment. Recommending commencement of ovarian stimulation using any of the available exogenous compounds without knowledge of individual ovarian potentials is simplistic and dangerous because of the possible adverse consequences for the woman. The identification of groups of patients likely to benefit from one protocol than another is central to the workup process of IVF. Determining the agents for ovarian stimulation as well as the combination of them, the daily dose and duration according to some background information should be seen as the way to enhance safety and cost-effectiveness. This discussion paper aims to introduce the concept of individualized ovarian stimulation in routine clinical practice and to generate interest for tailored stimulation protocols.
"Although some clinicians have reported that rLH administration prior to rFSH in IVF cycles increased the number of antral follicles, this did not translate into improved rates of live birth pregnancy.109 Thus, there is no evidence at the present time that co-administration of rLH to rFSH, in controlled ovarian hyperstimulation for IVF, has a beneficial effect in IVF. "
[Show abstract][Hide abstract] ABSTRACT: Recombinant human follicle stimulating hormone (rFSH) and luteinizing hormone (LH), also known as follitropin alpha and lutropin alpha, are manufactured by genetic engineering techniques which ensure high quality and batch to batch consistency. Follitropin alpha can be used for controlled ovarian hyperstimulation in assisted reproduction, ovulation induction for WHO group I and II anovulatory infertility and in men with hypogonadotrophic hypogonadism (HH) or idiopathic oligo-asthenospermia. Current evidence suggests superiority of urinary human menopausal gonadotropin (HMG) over follitropin alpha in controlled ovarian hyperstimulation for IVF in terms of live birth rate per couple. Addition of lutropin to follitropin alpha in an unselected IVF population does not appear to confer any benefit; however, it may have a role in ovulation induction in women with hypothalamic hypogonadism. Urinary HMG preparations (especially currently available highly purified preparations) are more cost effective than rFSH in terms of cost per ongoing pregnancy. However, women using rFSH injection pen devices have higher levels of satisfaction as compared to those using urinary HMG by means of conventional syringes.
"With this background, recent attempts of ovarian androgen priming have been developed on the basis that temporary exposure of follicles to increased levels of androgens may augment their responsiveness to FSH. LH, hCG, dehydroepiandrosterone, aromatase inhibitor and testosterone have been used mainly in the clinical setting of women with diminished ovarian reserve undergoing ovarian stimulation for IVF but results have been limited and inconclusive (Balasch et al., 2006; Barad and Gleicher, 2006; Massin et al., 2006; Durnerin et al., 2008; Lossl et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Studies in macaques have indicated that androgens have some synergistic effects with FSH on folliculogenesis. This study investigated the usefulness of pretreatment with transdermal testosterone in low-responder IVF patients.
Randomized clinical trial including 62 infertile women who had a background of the first IVF treatment cycle cancelled because of poor follicular response. Patients were randomized in two treatment groups in their second IVF attempt. In patients in Group 1 (n = 31), transdermal application of testosterone preceding standard gonadotrophin ovarian stimulation under pituitary suppression was used. In Group 2 (n = 31 patients), ovarian stimulation was carried out with high-dose gonadotrophin in association with a minidose GnRH agonist protocol. The primary end-point was the incidence of low-responder patients. The main secondary outcome was the incidence of patients reaching ovum retrieval.
The percentage of cycles with low response was significantly lower in Group 1 than in Group 2 (32.2 versus 71% 95% confidence interval for the difference, 15.7-61.6; P < 0.05). The number of patients with ovum retrieval tended to be higher in Group 1 than in Group 2 (80.6 versus 58.1% P = 0.09), the difference reaching statistical significance (81.2 versus 41.1%; P < 0.05) when only patients having normal basal FSH levels (16 and 17 patients in Groups 1 and 2, respectively) were considered.
Pretreatment with transdermal testosterone may improve the ovarian sensitivity to FSH and follicular response to gonadotrophin treatment in previous low-responder IVF patients. This approach leads to an increased follicular response compared with a high-dose gonadotrophin and minidose GnRH agonist protocol.
Human Reproduction 02/2009; 24(2):349-59. DOI:10.1093/humrep/den428 · 4.57 Impact Factor
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