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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online October 25, 2004 as doi:10.1096/fj.04-2271fje. |
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* Departments of Molecular Genetics,
Biological Regulation, and
Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel
2Correspondence: Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel. E-mail: menachem.rubinstein{at}weizmann.ac.il
SPECIFIC AIMS
Leptin induces release of pituitary gonadotropins by inducing hypothalamic GnRH. The goal of the present study was to study the possible existence of GnRH-independent effects of leptin on ovarian stimulation and follicular development.
PRINCIPAL FINDINGS
1. Leptin induces follicular development in ob/ob mice
The possible existence of GnRH-independent effects of leptin on ovarian stimulation and follicular development was studied in three mouse models of hypogonadism: GnRH-deficient hpg mice, leptin deficient ob/ob mice, and prepubertal C57BL/6 mice. To eliminate the known activity of leptin as an inducer of GnRH, all ob/ob and prepubertal mice were treated with the GnRH antagonist antide. Rapid follicular growth was seen 17 h after administration of leptin (two injections at an 8 h interval) to antide-treated ob/ob mice. This response was similar to one observed after administration of pregnant mare serum gonadotropin (PMSG). Concomitant treatment of ob/ob mice with PMSG and leptin resulted in interstitial cell growth and further ovarian growth. In contrast with ob/ob mice, leptin didn’t induce follicular development in hpg mice or antide-treated prepubertal mice.
2. Leptin induces formation of corpora lutea in hypogonadal mice
We tested the ability of leptin to replace LH as inducer of luteinization in three mouse models of hypogonadism after treatment with PMSG. Treatment of ob/ob mice with PMSG alone did not elicit formation of any corpora lutea (CL). In contrast, treatment of such mice with PMSG at time 0 followed by leptin at 48 h led to development of CL at 72 h (Fig. 1
A, arrow).
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PMSG induced follicular development in hpg mice as well. However, these CL exhibited abnormal morphology (Fig. 1C
). When hpg mice were treated with PMSG followed by leptin, a large number of CL were seen in all mice (Fig. 1D
). To check whether these effects of leptin could be obtained in normal mice, the study was repeated in antide-treated prepubertal C57BL/6 mice. Treatment of these mice with PMSG alone resulted in CL in only one-third of the mice, whereas treatment with PMSG followed by leptin gave rise to mature follicles and CL in all of the mice (Fig. 1G
). Mice treated with PMSG alone or PMSG and leptin exhibited CL with entrapped oocytes. These entrapped oocytes probably resulted from inefficient ovulatory response in the absence of LH surge.
3. Leptin induces ovulation in hypogonadal mice
Development of corpora lutea (CL) by PMSG followed by leptin in ovaries of all three mouse models of GnRH deficiency led us to test the possibility that leptin could replace hCG as an inducer of ovulation. To this end, we treated female hpg mice with PMSG daily for 4 days, followed on the fifth day by either saline or murine leptin. Microscopic examination of serial sections of oviducts isolated on the sixth day revealed that 4 of 10 mice ovulated, indicating a complete leptin-mediated process of ovulation (Fig. 2
A). No ovulation was detected upon treatment of the mice with PMSG alone.
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Similar results were obtained with normal, antide-treated prepubertal C57BL/6 mice (Fig. 2C
). No ovulation was detected upon treatment of the mice with PMSG alone. Similar results were obtained with antide-treated ob/ob mice treated first with PMSG and then with leptin. These observations indicated that leptin can replace hCG as an inducer of ovulation in mice, albeit with a much lower efficiency.
4. Serum progesterone is not elevated upon leptin-induced ovulation
To test whether leptin-induced ovulation was mediated by LH, we determined serum progesterone which serves as a robust marker of LH surge. No significant surge in serum progesterone was seen at 72 h in PMSG plus leptin groups of ob/ob and prepubertal mice, including those mice that ovulated. In a control experiment, prepubertal C57BL/6 mice treated with antide and PMSG at time 0 followed by hCG at 48 h gave the expected surge of serum progesterone. In a similar study, administration of PMSG followed by leptin did not elevate serum progesterone in PMSG primed hpg mice. These results suggest the existence of a leptin-induced mechanism of ovulation independent of LH surge.
The difference between hCG and leptin treatment was also noticed in the appearance of the mouse uterus. During pro-estrous and estrus days of the cycle, the uterus exhibits maximal distension due to high serum estradiol. This appearance was clearly observed in PMSG-treated mice. However, the distension and hyperemia subside after the LH surge (Tienhoven, 1968), as well as after administration of hCG, reflecting the decrease in serum estradiol and the concomitant increase in serum progesterone. In contrast, the uterus of ob/ob mice that ovulated upon leptin administration remained hyperemic, exhibiting maximal distension. In fact, treatment with leptin rendered the uterus hyperemic even in the absence of PMSG. The same uterine features were observed in antide-treated C57BL/6 mice and hpg mice. These differences in uterine physiology and appearance further support the notion that the leptin-induced ovulation is independent of LH activity.
5. Leptin induces the protease ADAMTS-1 in vitro
The preovulatory surge of LH induces ovulation by several mechanisms, including activation of proteases that weaken the follicular wall leading to rupture and extrusion of follicular content. These enzymes include a disintegrin and metalloproteinase with a thrombospondin-like motif (ADAMTS-1) and cathepsin L. We found by quantitative RT-PCR that leptin induced expression of ADAMTS-1 in isolated preovulatory follicles from C57BL/6 mice in vitro, thereby providing a mechanism for LH-independent ovulation.
CONCLUSIONS AND SIGNIFICANCE
Leptin has a critical role in reproduction, acting as an obligatory inducer of GnRH release. Our studies with three unovulatory mouse models show that leptin rapidly induces follicular development (in ob/ob mice), and formation of corpora lutea and ovulation in all three models of unovulation due to GnRH deficiency (Fig. 3
). This activity of leptin was independent of LH surge, as the GnRH axis was missing (hpg mice) or blocked by the GnRH antagonist antide (ob/ob and prepubertal mice). The LH-independent ovulation was further confirmed by the lack of increase in serum progesterone. Ovulation was probably triggered by leptin-induced ovarian protease ADAMTS-1. We conclude that in addition to its role in inducing GnRH, leptin can also mimic LH in its actions on the reproductive system, albeit at a lower efficacy. However, it should be mentioned that induction of ovulation by hCG (after PMSG) in ob/ob mice suggests that leptin is not essential for ovulation.
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Our in vivo results are supported by a previous study showing that leptin triggered maturation of mouse oocytes in vitro. Opposite results were reported as well, but they may be related to differences in timing. It was recently shown that hCG induces a dramatic but transient increase of leptin and its functional receptor in the ovary and this increase occurs immediately prior to ovulation. The mechanism of such ovulation may involve either a local effect of leptin on the ovary, such as induction of ADAMTS-1, or an as yet unknown hypothalamic pathway.
Our findings suggest a possible use of leptin in treatment of female infertility, particularly in subjects who do not respond properly to LH. Leptin may also be considered as a means to reduce the amount of FSH and LH given to induce ovulation in women who might be at risk of developing an ovarian hyperstimulation syndrome (OHSS), the most serious iatrogenic complication of fertility treatment.
FOOTNOTES
1 These authors contributed equally to this work. 
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-2271fje;
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