Obesity and fertility.

Obesity has an overall negative impact on fertility, affecting both women and men. Not only are obese individuals more likely to experience infertility, they are less likely to benefit from fertility treatment. Moreover, achieving pregnancy may place obese women at high risk for serious complications. It is important that obese individuals understand the effects that their obesity can have on reproductive function.

Gene expression profiling in the aging ovary.

DNA microarray is an important discovery technology that allows the analysis of the expression of thousands of genes at a time. Data from DNA microarrays elucidate fundamental biological processes through discovery of differential expression of genes not previously known or predicted to be involved in a particular process. In the ovary and other hormone-responsive tissues, the technology can be used to examine the effects of gene mutations, pharmaceutical agents, disease, hormones, developmental changes, or changes in gene expression related to aging.

Pioglitazone administration alters ovarian gene expression in aging obese lethal yellow mice.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) are often treated with insulin-sensitizing agents, e.g. thiazolidinediones (TZD), which have been shown to reduce androgen levels and improved ovulatory function. Acting via peroxisome proliferator-activated receptor (PPAR) gamma, TZD alter the expression of a large variety of genes. Lethal yellow (LY; C57BL/6J Ay/a) mice, possessing a mutation (Ay) in the agouti gene locus, exhibit progressive obesity, reproductive dysfunction, and altered metabolic regulation similar to women with PCOS. The current study was designed to test the hypothesis that prolonged treatment of aging LY mice with the TZD, pioglitazone, alters the ovarian expression of genes that may impact reproduction. METHODS: Female LY mice received daily oral doses of either 0.01 mg pioglitazone (n = 4) or an equal volume of vehicle (DMSO; n = 4) for 8 weeks. At the end of treatment, ovaries were removed and DNA microarrays were used to analyze differential gene expression. RESULTS: Twenty-seven genes showed at least a two-fold difference in ovarian expression with pioglitazone treatment. These included leptin, angiopoietin, angiopoietin-like 4, Foxa3, PGE1 receptor, resistin-like molecule-alpha (RELM), and actin-related protein 6 homolog (ARP6). For most altered genes, pioglitazone changed levels of expression to those seen in untreated C57BL/6J(a/a) non-mutant lean mice. CONCLUSION: TZD administration may influence ovarian function via numerous diverse mechanisms that may or may not be directly related to insulin/IGF signaling.

Declining fertility in the lethal yellow mouse is related to progressive hyperleptinemia and leptin resistance.

Mice possessing the lethal yellow mutation (C57BL/6J A(y)/a) become obese and develop hyperleptinemia and leptin resistance as they age. To determine the relationship between altered leptin physiology and reproductive function in these mice, we compared body weight (BW), serum leptin concentration, ovulation rate, and in vitro blastocyst development among 120- and 180-d-old lethal yellow and black non-mutant (a/a) mice. Estrous female yellow and black mice were mated with fertile black males. Oviducts were flushed approximately 36 h after mating and the recovered embryos were cultured for 96 h. BW, serum leptin levels, and the leptin:BW ratio differed among groups as follows: 180-d yellow > 120-d yellow > 180-d black = 120-d black. Ovulation rate was similar among 120-d yellow and black, and 180-d black mice. Among 180-d yellow mice, five of twelve mice failed to ovulate, but the other seven mice ovulated a similar number of oocytes as their black counterparts (8.4 +/- 0.9 versus 8.0 +/- 1.3). Non-ovulators had higher (P < 0.05) leptin levels (56.6 +/- 1.8 ng x mL(-1)) than ovulators (46.2 +/- 3.5), but BW did not differ significantly. Fewer embryos from 180-d yellow mice reached the blastocyst stage in culture than did the embryos from black mice (55% versus 83%, P < 0.05). Moreover, blastocyst development in 180-d old yellow mice negatively correlated with leptin levels (r = -0.797, P = 0.032) and leptin:BW ratio (r = -0.847, P = 0.016), but not with BW. Declining reproductive function in lethal yellow mice appears to be related to increasing levels of leptin and progression of leptin resistance.

Relationship between the outcomes of assisted reproductive techniques and sperm DNA fragmentation as measured by the sperm chromatin structure assay.

OBJECTIVE: To investigate how moderate and/or high levels of DNA fragmentation (DFI), as measured by the sperm chromatin structure assay (SCSA), affect either IVF or IVF with intracytoplasmic sperm injection (ICSI) fertilization, cleavage, blastulation, implantation, and pregnancy. DESIGN: Retrospective clinical study. SETTING: Academic human reproduction laboratory. PATIENT(S): Eighty-nine couples undergoing IVF with conventional fertilization or ICSI. INTERVENTION(S): Sperm chromatin structure assay testing (SCSA) of semen aliquot taken from ejaculate used for assisted reproductive technology (ART). MAIN OUTCOME MEASURE(S): Related DFI to conventional semen parameters and cycle-specific outcomes after ART. RESULT(S): No patients achieved clinical pregnancy if SCSA values exceeded the DFI (27%, P<.01), moderate DFI (15%, P<.01), or high DFI (15%, P<.05) thresholds. Dividing the DFI sperm population into moderate-fragmentation and high-fragmentation categories did not improve the prognostic value of the SCSA. No coefficient of determination (r(2)) between SCSA parameters and conventional parameters exceeded 0.29. CONCLUSION(S): Sperm chromatin structure assay identified thresholds for negative pregnancy outcome after ART not identified using conventional semen parameters. This is the first study analyzing the clinical value of sperm DFI to [1] include a large number of ART patients (n = 89), [2] perform SCSA analysis on a semen aliquot from the ejaculate used for ART, and [3] examine how the extent (moderate and high DFI) of DFI influenced ART outcomes.

Leptin and ovarian folliculogenesis: implications for ovulation induction and ART outcomes.

Leptin participates in regulation of ovarian folliculogenesis indirectly via control of luteinizing hormone and follicle-stimulating hormone secretion. More recent evidence suggests that leptin also has direct regulatory actions on the developing follicle. The presence of leptin receptors on follicular cells, including oocytes, and early preimplantation embryos suggests that leptin may play a direct physiologic role in follicular maturation, oocyte development, and early cleavage. Because circulating leptin levels are directly related to body adiposity, elevated leptin concentrations associated with obesity may partly explain the negative impact of obesity on fertility. The influence of leptin on follicular development and oocyte maturation has important implications for ovulation induction and assisted reproductive technologies. Moreover, polycystic ovarian syndrome may be associated with altered leptin phsyiology.

DNA microarray analysis of gene expression markers of endometriosis.

OBJECTIVE: To use DNA microarray technology to examine differential gene expression in uterine endometrium versus endometriosis implants. DESIGN: Pilot study. SETTING: Volunteers in an academic research environment. PATIENT(S): Premenopausal women scheduled for surgery for suspected endometriosis. INTERVENTION(S): Surgical excision of endometriosis tissue and uterine endometrial biopsy. MAIN OUTCOME MEASURE(S): Gene expression. RESULT(S): The expression of eight genes from a total of 4,133 genes on the DNA microarray was increased in endometriosis implants compared with uterine endometrium. The eight genes were beta-actin, alpha-2 actin, vimentin, 40S ribosomal protein S23, Ig-lambda light chain, Ig germline H chain G-E-A region gamma-2 constant region gene, major histocompatibility complex class 1,C, and complement component 1 S subcomponent. CONCLUSION(S): The data demonstrate that the DNA microarray is an effective tool for the identification of differentially expressed genes between uterine and ectopic endometrium; further study of the genes identified herein will expand our understanding of the nature of endometriosis and assist in the eventual development of new treatments for endometriosis.