Serum and follicular fluid leptin during in vitro fertilization: Relationship among leptin increase, body fat mass, and reduced ovarian response

The satiety factor leptin is expressed in several reproductive tissues, but its role in the control of reproductive physiology is not well understood. We studied leptin concentrations in the sera and follicle fluids of 52 wom en [body fat mass percentage (BFM%) range, 19.6-38.8%] undergoing pituitary down-regulation and ovarian hyperstimulation for in vitro fertilization (I VF) treatment. Fasting serum samples were collected 1) at maximal suppressi on before the initiation of gonadotropin treatment, 2) at maximal ovarian h yperstimulation, 3) at the time of oocyte retrieval, and 4) 16 days later w hen all subjects were under exogenous luteal support using 600 mg progester one daily. Follicular fluid (FF) was obtained at oocyte retrieval from two representative preovulatory follicles in both ovaries. During ovarian hyper stimulation there was a significant 60% increase in serum leptin concentrat ions from 10.9 +/- 1.1 (SEM) to 15.7 +/- 1.5 ng/mL (P < 0.01) between suppr ession and maximal hyperstimulation, demonstrating that the ovarian functio nal state can affect serum leptin concentrations. A serum leptin increase o f 22-198% during ovarian hyperstimulation was evident in 43 subjects, where as in 9, leptin concentrations remained unchanged. A positive correlation b etween leptin change and BFM% (r = 0.55; P < 0.0005) was observed in the 43 leptin responders. The follicular fluid leptin level was similar to that i n serum. In separate linear regression analysis, BFM% contributed to 59-64% , body mass index to 46-56%, and weight to 46-55% (all P < 0.001) of the va riability in leptin concentrations at the 4 time points. The 20-fold increa se in serum estradiol concentrations during IVF was not significantly corre lated with changes in leptin concentrations. On the contrary, the relative serum leptin increase was negatively associated with the ovarian response t o hyperstimulation, as revealed by the numbers of follicles (b = -0.28; r(2 ) = 8.1%; P < 0.05) and oocytes retrieved (b = -0.39; r(2) = 15.2%; P < 0.0 1). This relationship was further reflected in a positive correlation betwe en the percent increases in leptin and FSH concentrations (r = 0.39; P < 0. 01). The significant relationship of high leptin and reduced ovarian respon se was also maintained when the cumulative dose of FSH was used as a covari able. Reduced ovarian response was not a function of body mass index, BFM%, basal leptin levels, or insulin concentrations. Fasting serum insulin conc entrations remained unchanged in response to IVF, but were positively corre lated to serum leptin concentrations at all four time points. Our data suggest that leptin production may be influenced by the ovarian fu nctional state. During IVF a high relative leptin increase is associated wi th adiposity and a reduced ovarian response. These observations support the possibility that high leptin concentrations might reduce ovarian responsiv eness to gonadotropins. Hence, leptin might explain in part why obese indiv iduals require higher amounts of gonadotropins than lean subjects to achiev e ovarian hyperstimulation.