friday_session 13_hugues

NO EFFECT OF LH ACTIVITY ON PROGESTERONE RISE Jean-Noël Hugues, France Reproductive Medicine Unit - Jean Verdier Hospital Bondy 93.143 - University Paris XIII - France The issue of the premature rise in serum progesterone (P) during controlled ovarian stimulation is still a matter of several controversies. As recently emphasized, the serum P rise observed during the final part of COS is not actually a premature luteinization because it takes place in patients treated with GnRH analogs which fully control further LH surge. Many factors have been associated with an increased risk of P rise during GnRH analog controlled cycles such as the total dose of FSH administered as well as the intensity of the ovarian response assessed by serum E2 levels and the number of follicles or oocytes. Therefore, it is well recognized that the increase in “granulosa cells” activity is the main driver of P elevation which usually occurs during the last few days of the ovarian stimulation. To assess the potential involvement of LH in the P rise, it is essential to consider separately the effects of LH on theca and granulosa cells. • On the one hand, LH acts on constitutive receptors of theca cell to stimulate Cytochrome P450 CYP 17 enzymatic complex, responsible for the conversion of progesterone or pregnenolone to 17-hydroxylated products and androgens, resulting in decreased P production. In contrast, LH stimulates 3β HSD type II to increase P production by conversion of pregnenolone to P. Therefore, the overall effect of LH on theca cell P production depends on these respective enzymatic activities. • On the other hand, LH, in synergy with FSH, strongly stimulates P production by granulosa cells throughout LH receptors induced by FSH during the late follicular phase This complex biphasic and development-related effect of LH on P production is likely to explain the controversy regarding the role of LH in serum P elevation at the time of hCG administration (PhCG). Few studies have been published so far on the role of endogenous LH environment. Some of them concluded for the lack of correlation between serum progesterone elevation and LH values during ovarian stimulation. In contrast, a close relationship between serum LH and P rise in GnRH agonist cycles has been recently reported by Yding Andersen et al. We have also reported the results of a retrospective analysis to assess the correlation between the LH endogenous environment and the incidence of P rise. For that purpose, we compared the consequences on serum PhCG of different endogenous LH environments created by GnRH agonist and antagonist protocols. Serum PhCG were significantly higher in patients treated with GnRH agonist protocols and a significant correlation was observed with serum LH levels during the last part of the stimulation. According to the multi-variate analysis of over 700 cycles, the main factors involved in serum PhCG elevation were the total FSH dose as well as the serum estradiol on hCG day. Therefore, the lower serum PhCG values observed in patients treated with GnRH antagonist regimen is mainly explained by the reduced follicular recruitment and steroidogenic activity usually observed with this protocol. However, the different LH environment created by two GnRH analogs regimens during the late stage of COS is likely to participate in the difference between serum PhCG concentrations. What about the consequences of “LH activity” supplementation on serum PhCG ? To address this issue, we performed a systematic review of 108 studies published between 1980 and 2010, dealing with the hormonal consequences of ovarian stimulation by FSH alone or in addition with “LH activity” products (hMG, r.LH, hCG). Serum PhCG determination was reported in only 34 studies. In a vast majority, no significant difference in serum PhCG could be found between stimulation regimens However, in 4 studies where LH activity (3 hMG and 1 r.LH) was administered from day 1 of ovarian stimulation, serum P values were significantly decreased. In contrast, in 2 studies where LH activity (hCG) was provided during the late follicular phase, serum P values were significantly increased. Analysis of confounding factors allowed to conclude that the intensity of ovarian stimulation is the most important determining factor to explain serum PhCG rise. Therefore, this systematic review shows that providing “LH activity” supplementation in combination with FSH during ovarian stimulation does not have any consistent effect on serum PhCG concentrations. It also allows to speculate that the timing of ‘LH activity” administration (day 1 of stimulation or during the late follicular phase) can influence its impact on serum P changes. In conclusion, these data show that LH does not play a major role in serum PhCG rise during controlled ovarian stimulation. However, the positive correlation observed between serum PhCG and endogenous LH environment or “LH activity” supply in the final part of stimulation attests for a stimulatory effect of LH on granulosa cells of mature follicles. Additional studies are required to confirm the assumption, also derived from physiology, that the consequences of “LH activity” supply may actually differ according to the timing of administration.