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Model of Inflammation applied to Infertility and Adverse Pregnancy Outcomes: Different sources and their interactions John L. Couvaras, M.D. Reproductive Endocrinologist, B.C.
INFERTILITY INFERTILITY WORKUP Checking of Ovulation Semen Parameter Tubal Status Uterine Cavity Normalcy
INFERTILITY Current conventional treatment approach for infertile patient without severe male factor or blocked tubes. Super-ovulation Operate Super-ovulation IVF / ICSI
UNEXPLAINED INFERTILITY Cochran Database articles 2002 & 2005 Treatment of sub-fertility with IVF shows no conclusive benefits Overall prognosis with current treatment of infertility by Collins et al. Human Reproduction Update, Vol. 10, No.4 pp. 309-316, 2004 Typical management of infertility would fall short of 50% live births even with extensive utilization of ART. Underlying unknown untreatable factors remain barriers to greater overall success in the treatment of infertility.
Life table analysis of outcomes In 2004, 126 patient came in for evaluation and 36 did not remain, leaving 90 patients. 12 of 90 were lost to followup without treatment 10 of 14 did IVF and delivered. This is 71% 39 of 64 who remained for non-ART treatment went on to deliver. This is 61% 49/78 total patients is 62.8% went on to deliver Collins et al: Out of 10,000 patients worked up for infertility, 4900 did not stay for treatment, but 30% were pregnant within 2 years. Of the 5100 who remained for treatment, 42% achieved ongoing pregnancy without using IVF. Even with extensive IVF usage, pregnancies did not exceed 50% of the treatment group.
Live birth rates estimated in 20 studies involving follow-up of 14,460 infertile couples,1950-2003. Do not include IVF or ICSI treatment. Overall prognosis with current treatment of infertility, John A Collins et al.
INFERTILITY Per Cycle Fecundity Rate As low as 0.5% chance/cycle conceiving spontaneously if unexplained. With Clomid alone – Increases to 4% / cycle Clomid + IUI – 7% / cycle HMG & IUI – 17% / cycle Cumulative Pregnancy Rate, short of IVF – 42% / cycle AT IVF PHOENIX Ongoing cumulative pregnancy rate 61% without using IVF
I began looking for other things to explain the infertility, other than simply getting gametes together. Infertility patients have 3-5X more Adverse Pregnancy Outcomes than the general population.
Unexplained RSA patients In the early 1990s we were using low dose heparin and noticed Increased delivery rates. Less migraines Less hyperemesis Warmer hands and less livido
UNEXPLAINED INFERTILITY Arginine i NOS Arginase Nitric Oxide (NO) Polyamine Heparin vasodilated via NO
INFERTILITY Elevated Day 3 FSH Levels - >11 Abnormal Clomiphene Citrate Challenge Test (CCCT) Negative Predictive value Elevated Day 3 FSH level, not just alive or dead ovaries. Dynamic Ovaries Deaf Ovaries--------due to Hormone Transmission Defect. (FSH or IGF-1) Depleted Ovaries----due to lack of visible basal antral follicles Dead Ovaries----due to lack of any primordial follicles. Simple Vasodilation Hormone Transmission Defects Normalized Improved Ovarian response Improved Pregnancy Rates
INFERTILITY Viral Insult Herpes virus family Chronic low grade viral infection Immune suppression Enhance TH1 activation After doing viral protocol, 50% of infertile couples (excluding severe male factor and tubal blockage) conceive within 4 cycles, without IVF
25% of infertile and RSA patients. IGF-1 is permissive to follicle maturation IGF-1 reverses eNOS uncoupling in DM and Insulin resistance.
INFERTILITY T Helper Cell 2 (TH2) overexpression 23 Patients failed after all approaches TNF alpha <1.0 in 100% of these extreme failures TNF alpha normalized in all, and – 6/13 patients who retried superovulation were able to conceive. Mostly secondary infertility
Biological Response Modifiers IVIG: may work to remove virally infected WBC WBC immunizations or Killed Steptococcal preps: believed to reset TH1/TH2 responses. These were introduced for early clinical miscarrying patients, but I have found that this is most helpful in Early Implantation Failure patients. (currently not available in USA) Recalcitrant thin endometrium---70% improve Chemical lossesmoves to clinical pregnancy in 70% Unexplained infertility-no signs of pregnancy but patient feels something around 7-11 days after ovulation.
So How Do I Make Sense of all of this. Infertility/RSA patients have 3-5x risk of APO over general population. Treating for clotting imbalances and viruses and immune dysfunction improves infertility outcomes by 50%, without using IVF. Inflammation can be due to all of these sources. These sources are affecting nitric oxide balance. Nitric oxide balance may regulate inflammation. Inflammation may causing infertility and APO.
Inflammation effect on NO. Defects in metabolism of Essential Fatty Acids, BH4, eNOS/Arginase expression or activity Less Nitric Oxide produced per unit time. Hereditary defects in clotting balance, or acquired defects lead to I/R injury and ROS. More Nitric Oxide consumed/destroyed per unit time and less delivered. Viral insults creates endothelial cell vasculitis, and virus affects anti/pro inflammatory prostanoid balance. Prostanoid balance and metabolism is regulated through Nitric Oxide.
Therapeutic interventions into Inflammatory processes. Improved NO formation via replacement of BH4, heparin/lovenox stimulation on NOS. Add L-arginine substrate Limit S-nitrosylation of cysteine from Increasing Arginase Km Detox homocysteine with folate, prevent cysteine Limit ROS and Fe lowering of Arginase Km Decrease NO removal via lowering ROS Antioxidants/exercise/diet-good EFA metabolism Low dose allopurinol to block Xanthine Oxidase Less uric acid means less WBC ROS formation Less XO means less OH- and O2-. Less ROS, means less NO quenching Less ROS, means less BH4 destruction. Less ROS, means higher Arginase Km
Therapeutic interventions into Inflammatory processes. Improved NO formation via replacement of BH4, heparin/lovenox stimulation on NOS. Add L-arginine substrate Limit S-nitrosylation of cysteine to limit decrease Arginase Km Limit ROS and Fe lowering of Arginase Km Decrease NO removal via lowering ROS Antioxidants/exercise/diet Low dose allopurinol to block Xanthine Oxidase Less uric acid means less WBC ROS formation Less ROS, means less NO quenching Less ROS, means less BH4 destruction. Less ROS, means higher Arginase Km