Home | Pregnancy Timeline | News Alerts |News Archive Nov 17, 2014
LEFT Carnegie Stage 3 - The Early Blastocyst
RIGHT Carnegie Stage 4 - Implantation Begins
Image credit: The Visible Embryo
Slowing a woman's biological clock
Neutralizing an immune system gene could improve fertility treatments for older women.
Difficulty in conceiving a child is a challenge for one in seven heterosexual couples in America, especially when over the age of 35. Now researchers at Tel Aviv University (TAU) and Chaim Sheba Medical Center at Tel Hashomer, Israel, believe they can boost the chances of conception in women undergoing in vitro fertilization (IVF) treatments.
Research reveals a link between our innate immune system — the one we are born with — and our uterine response to the implanting of a fertile egg.
The study, published recently in the Proceedings of the National Academy of Sciences, is the doctoral thesis work of Dr. Shiri Uri-Belapolsky at the Sackler School of Medicine, Tel-Aviv University (TAU) .
According to research with laboratory mice, deleting the protein Interleukin-1 (IL-1), key in our innate immune system response mechanism, could improve the number of eggs available for fertilization as well as improve our ovarian response to In-Vitro Fertilization stimulation.
Dr. Uri-Belapolsky: "Our study shows that neutralizing the effects of the IL-1 protein, slows down the natural processes that destroy eggs. These results may promote development of new treatments, such as creation of an IL-1 block."
A connection between Interleukin-1 and fertility was found by accident. Research in mice on the role of IL-1 in atherosclerosis — or hardening of the arteries — produced a surprising result. The length of fertility of IL-1-deficient mice increased by 20% over control mice.
All female mammals, including humans, are born with a finite number of eggs which are subject to biological timing dictating an end to fertility. In humans, female fertility ends around 50 years of age.
Over the past decade, a trend in postponing child-
bearing has led to an increase in IVF treatments
where mechanical injury of the endometrium can
increase receptivity of the uterus to the 4 day old
fertile egg (or blastocyst) implanting within.
Breaking apart the endometrial layer of the uterus
stimulates the formation of dendritic cells (DCs).
Dendritic cells act as messengers between the innate (born with) and the adaptive (acquired) immune systems. DCs have a very large surface area covered with antigens to prevent T cells of the immune system from attacking the implanting blastocyst as if it were a hostile invader.
"Identifying Interleukin-1 as a possible culprit in run-a-way inflammation, may offer new insight into the mechanisms responsible for egg loss and a practical intervention."
Ruth Shalgi PhD, professor, Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Israel
Females are subjected to a biological clock that dictates the end of the reproductive lifespan, on average, at 50 y of age, whereas fecundity sharply decreases after 30 y of age. Over the past decade, a current trend of postponing childbearing into advanced age has led to a corresponding upward trend in the number of in vitro fertilization (IVF) treatments. Inflammation was reported to affect both IVF outcomes and the ovarian reserve adversely. Identifying a possible culprit, such as IL-1, may offer new insight into the mechanisms responsible for oocyte loss as well as practical interventions, such as IL-1 blockade, which aims to slow down the rate at which oocytes are eliminated and improve IVF outcomes.
Oocyte endowment dwindles away during prepubertal and adult life until menopause occurs, and apoptosis has been identified as a central mechanism responsible for oocyte elimination. A few recent reports suggest that uncontrolled inflammation may adversely affect ovarian reserve. We tested the possible role of the proinflammatory cytokine IL-1 in the age-related exhaustion of ovarian reserve using IL-1α and IL-1β–KO mice. IL-1α–KO mice showed a substantially higher pregnancy rate and litter size compared with WT mice at advanced age. The number of secondary and antral follicles was significantly higher in 2.5-mo-old IL-1α–KO ovaries compared with WT ovaries. Serum anti-Müllerian hormone, a putative marker of ovarian reserve, was markedly higher in IL-1α–KO mice from 2.5 mo onward, along with a greater ovarian response to gonadotropins. IL-1β–KO mice displayed a comparable but more subtle prolongation of ovarian lifespan compared with IL-1α–KO mice. The protein and mRNA of both IL-1α and IL-1β mice were localized within the developing follicles (oocytes and granulosa cells), and their ovarian mRNA levels increased with age. Molecular analysis revealed decreased apoptotic signaling [higher B-cell lymphoma 2 (BCL-2) and lower BCL-2–associated X protein levels], along with a marked attenuation in the expression of genes coding for the proinflammatory cytokines IL-1β, IL-6, and TNF-α in ovaries of IL-1α–KO mice compared with WT mice. Taken together, IL-1 emerges as an important participant in the age-related exhaustion of ovarian reserve in mice, possibly by enhancing the expression of inflammatory genes and promoting apoptotic pathways.
Dr. Shiri Uri-Belapolsky's research was led by Prof. Ruth Shalgi, of the Department of Cell and Developmental Biology at TAU's Sackler School of Medicine, Dr. Yehuda Kamari and Prof. Dror Harats of TAU's Sackler Faculty of Medicine and Sheba Medical Center, and Dr. Aviv Shaish of Sheba Medical Center.
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