Misc. research

This is where I “dump” all my research from the intertubes.

Couple topics here- Adding DHEA is bad; Melatonin and Myo-inositol for egg quality; acupuncture for IVF; “Vitamin” D is a hormone you’re probably deficient in, IVIg and Humira to reduce cytokine inflammation…. more to come.
* * * * *

from http://www.preventmiscarriage.com/Blog/2012/December/Increased-DHEA-linked-to-Poor-Decidualization.aspx

“A group in Washington recently published an article that links increased DHEA found in patients with PCOS with poor decidualization – the failure to properly prepare the endometrial lining for pregnancy. The article showed that high levels of DHEA found in PCOS patients led to poor decidualization by inhibiting an enzyme necessary for proper development of the decidua, this enzyme is called G6PD. Proper decidualization is determined by measuring levels of markers in the endometrium that were associated with normal development of decidua (PRL and IGFBP1).

DHEA administration lowered the levels of these markers and may be the mechanism by which PCOS affects implantation and leads to the significantly higher rate of miscarriage in this group of patients (it is also interesting to note that Lovenox treatment increases the production of these same markers, and may be the mechanism for its success in PCOS patients not related to its anti-coagulation affect). Metformin treatment has also been shown to reverse this effect of DHEA.

Individuals using DHEA supplements to improve egg quality and to increase egg numbers should also be aware of these issues negative affects on the endometrium as well. This continues to make it clear that a thorough understanding of all the mechanisms of how PCOS syndrome can lead to miscarriages is necessary for the correct treatments to be administered. ”

* * * * * * * * * * *

Natural food sources of myo-inositol: cantaloupe, oranges, grapefruit, and beans are pretty high!
http://www.ajcn.org/content/33/9/1954.full.pdf

Myo-inositol and Melatonin are efficient predictors for oocyte quality and IVF outcomes: indeed, high concentration of both molecules positively correlates  with high oocyte quality. In particular, several  clinical trials have shown that  supplementation  with MI, alone or in association with melatonin,  is a practical approach able to improve oocyte quality and IVF outcomes in both PCOS patients and normal subjects.”
http://www.europeanreview.org/article_download/929

http://humrep.oxfordjournals.org/content/17/6/1591.full

DO NOT TAKE D-CHIRO-INOSITOL!!  Total r-FSH units increased significantly in the two groups that received the higher  doses of  DCI. The number of immature oocytes was significantly increased in the three groups that received the higher  doses of DCI. Concurrently, the number of MII oocytes was significantly lower in the D group compared to placebo  group. Noteworthy, the number of grade I embryos was significantly reduced by DCI supplementation. Indeed,  increasing DCI dosage progressively worsens oocyte quality and ovarian response.
http://www.ovarianresearch.com/content/pdf/1757-2215-5-14.pdf

Our findings suggest that the addition of myo-inositol to folic acid in non PCOS-patients undergoing multiple follicular stimulation for in-vitro fertilization may reduce the numbers of mature oocytes and the dosage of rFSH whilst maintaining clinical pregnancy rate. Further, a trend in favor of increased incidence of implantation in the group pretreated (daily dose of 4,000 mg of myo-inositol into two administrations/day in addition to 400 μg of folic acid for the 3 months before and during rFSH administration) with myo-inositol was apparent in this study. Further investigations are warranted to clarify this pharmacological approach, and the benefit it may hold for patients. However, this study is underpowered to evaluate IVF outcomes like implantation and clinical pregnancy with the mechanism of improved oocyte competence.
http://www.rbej.com/content/10/1/52

Protocol: 4 g myo-inositol a day combined with 200 mg folic acid and 3 mg melatonin administrated continuously from the day of GnRH administration. In patients undergoing IVF that have  reported low oocyte quality in previous cycles, the treatment with melatonin plus myo-inositol and folic acid, compared with myo-inositol plus folic acid alone, reduced the number of germinal vesicles and degenerated oocytes and enhanced the number of morphologically mature oocytes at ovum pick-up without compromising the total number of retrieved oocytes. An important result is also the greater number of top-quality embryos  in the group cotreated with melatonin. The number of total pregnancies registered is higher in patients cotreated with melatonin but the results are not statistically significant perhaps because the little number of patients recruited. These results  are in line with other studies, suggesting the positive effect that melatonin plays on oocyte quality and pregnancy outcome.
http://www.europeanreview.org/article_download/780

How to get MYO-inositol instead of generic inositol or worse, d-chiro-inositol…. I have had a very hard time discerning supplements online and worse, the muscle-bound bozo in the local GNC, Total Nutrition, etc type of store is clue-free on the different types of inositol. Inofolic is available outside the US:
http://www.inofolic.it/drupal/?q=node/48

And in the US it’s available as Pregnitude through Amazon (you won’t find it available on Amazon, must go through the Pregnitude website.) $35, free shipping, for a month’s worth.
http://www.pregnitude.com/

* * * * *

ACUPUNCTURE and IVF

An acupuncturist I considered using sent me two links to reassure me of its utility:Acupuncture helps insomniacs.
http://www.ncbi.nlm.nih.gov/pubmed/22903446
and
http://www.ncbi.nlm.nih.gov/pubmed/20638338 (acupuncture on the day of embryo transfer has no statistical effect)
Then I did additional research– I went to PubMed and typed acupuncture IVF.  Here’s everything, the good and bad, except a couple articles using Acupuncture for pain relief during ER instead of anesthesia, and a couple articles that had no abstract available and were in a foreign language.
Acupuncture can help if done right but if done in the wrong spots, can have an adverse effect on ART outcome. And the spots are hard to define and numerous.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3395377/?tool=pubmed
Double blind randomized study reveals placebo acupuncture was associated with a significantly higher overall pregnancy rate when compared with real acupuncture.
http://www.ncbi.nlm.nih.gov/pubmed/18940896
Research insufficient to show benefit so far; description of planned future study, dated May 2012.
http://www.ncbi.nlm.nih.gov/pubmed/22607192
No significant benefits of acupuncture are found to improve the outcomes of IVF or ICSI.
http://www.ncbi.nlm.nih.gov/pubmed/22540969Electroacupuncture can increase the contents of HLA-G in the body and the level of HLA-G secreted in embryos for the patients in the process of IVF-ET. The clinical effects of electroacupuncture for the patients of kidney deficiency and liver qi stagnation are better than those for the patients of phlegm dampness. But there were no significant differences in clinical pregnancy rate, fertilization rate and cleavage rate among three groups.
http://www.ncbi.nlm.nih.gov/pubmed/22493912For PCOS patients, Clinical pregnancy rate (46.67%, 14/30) in electroacupuncture + injectibles group was higher than that (37.93%, 11/29) in control (no acupuncture) group, but without statistical difference. Stem cell factor levels in the serum and follicular fluid on the day of ovary collection were higher obviously than those in control group.
http://www.ncbi.nlm.nih.gov/pubmed/21894688

Transcutaneous electrical acupoint stimulation (not acupuncture), especially double TEAS (30 min before and after ET, either FET or fresh), significantly improved the clinical outcome of ET. The live birth rate basically doubled with double TEAS. 309 study participants under age 45.
http://www.ncbi.nlm.nih.gov/pubmed/21862001

Could only find the abstract, not the full text, but it said:
Acupuncture may improve ovulation by modulating the central and peripheral nervous systems, the neuroendocrine and endocrine systems, the ovarian blood flow, and metabolism. Secondly, acupuncture can improve the outcome of IVF-ET, and the mechanisms may be related to the increased uterine blood flow, inhibited uterine motility, and the anesis of depression, anxiety and stress. Its effect on modulating immune function also suggests helpfulness in improving the outcome of IVF-ET. Finally, the studies suggest that acupuncture plays a positive role in male infertility, the mechanism of which is not yet clear.
http://www.ncbi.nlm.nih.gov/pubmed/21611904

New emerging evidence from clinical trials demonstrates that acupuncture performed at the time of embryo transfer does not improve the pregnancy or live birth outcome after treatment.
http://www.ncbi.nlm.nih.gov/pubmed/20650689

Live birth rate 5% higher in non-acupuncture group. (Age <38, day of ET)
http://www.ncbi.nlm.nih.gov/pubmed/20638338

Non-egg-donor recipients (57 patients total) potentially had an improvement in clinical pregnancy rate with acupuncture (35.5% without acupuncture vs. 55.6% with acupuncture). Live birth rate unknown.
http://www.ncbi.nlm.nih.gov/pubmed/20621276

60 patients total. The pregnancy rate in the acupuncture group was higher than that in the control group, and the abortion rate in the observation group was lower than that in the control group, but there was no statistically significant difference between the two groups.
http://www.ncbi.nlm.nih.gov/pubmed/19873910

Electroacupuncture could be useful for reducing uterine artery blood flow impedance, but did not increase the pregnancy rate in patients undergoing IVF.
http://www.ncbi.nlm.nih.gov/pubmed/19574177

Cortisol levels in Acupuncture group were significantly higher on IVF medication days 7, 8, 9, 11, 12, and 13 compared with controls. Prolactin levels in the Ac group were significantly higher on IVF medication days 5, 6, 7, and 8 compared with controls. In this study, there appears to be a beneficial regulation of cortisol and prolactin in the Ac group during the medication phase of the IVF treatment with a trend toward more normal fertile cycle dynamics.
http://www.ncbi.nlm.nih.gov/pubmed/19118825

Currently available literature does not provide sufficient evidence that adjuvant acupuncture improves IVF clinical pregnancy rate.
http://www.ncbi.nlm.nih.gov/pubmed/18652588

The use of acupuncture in patients undergoing IVF was not associated with an increase in pregnancy rates but they were more relaxed and more optimistic.
http://www.ncbi.nlm.nih.gov/pubmed/18314118

Acupuncture performed twice weekly during the follicular and luteal phase does not seem to improve pregnancy rates following IVF-ET.
http://www.ncbi.nlm.nih.gov/pubmed/17937084

Limited but supportive evidence from clinical trials and case series suggests that acupuncture may improve the success rate of IVF and the quality of life of patients undergoing IVF and that it is a safe adjunct therapy. However, this conclusion should be interpreted with caution because most studies reviewed had design limitations, and the acupuncture interventions employed often were not consistent with traditional Chinese medical principles. The reviewed literature suggests 4 possible mechanisms by which acupuncture could improve the outcome of IVF: modulating neuroendocrinological factors; increasing blood flow to the uterus and ovaries; modulating cytokines; and reducing stress, anxiety, and depression.
http://www.ncbi.nlm.nih.gov/pubmed/17515023

Twenty two patients (average age 36.2 years) were treated over a total of 26 IVF cycles and 15 pregnancies were achieved, as determined by presence of foetal heartbeat on ultrasound at four weeks post embryo transfer. This was a success rate of 57.7% compared with 45.3% for patients in the IVF unit not treated with acupuncture (P > 0.05). Relaxing effects were noted following acupuncture and it is speculated that this may have contributed to the increase in pregnancy rate for the acupuncture group.
http://www.ncbi.nlm.nih.gov/pubmed/16618046

Luteal phase acupuncture after IVF/ICSI resulted in clinical pregnancy rate and ongoing pregnancy rate (33.6% and 28.4%, respectively) that were significantly higher than in the control group (15.6% and 13.8%).
http://www.ncbi.nlm.nih.gov/pubmed/16616748

Acupuncture on the day of ET significantly improves the reproductive outcome of IVF/ICSI, compared with no acupuncture. Repeating acupuncture on ET day +2 provided no additional beneficial effect.
http://www.ncbi.nlm.nih.gov/pubmed/16600232

For those subjects receiving acupuncture, the odds of achieving a pregnancy were 1.5 higher than for the control group, but the difference did not reach statistical significance. The ongoing pregnancy rate at 18 weeks was higher in the treatment group (28% vs. 18%), but the difference was not statistically significant. There was no significant difference in the pregnancy rate between groups; however, a smaller treatment effect can not be excluded. Our results suggest that acupuncture was safe for women undergoing ET.
http://www.ncbi.nlm.nih.gov/pubmed/16600225

Certain effects of acupuncture are mediated through endogenous opioid peptides in the central nervous system, particularly beta-endorphin. Because these neuropeptides influence gonadotropin secretion through their action on GnRH, it is logical to hypothesize that acupuncture may impact on the menstrual cycle through these neuropeptides.
http://www.ncbi.nlm.nih.gov/pubmed/12477502

 http://yourivfacupuncture.com/what-is-the-process/research/
* * * * * *Vitamin D!
http://drgominak.com/vitamin-d

Vit­a­min D is not a vit­a­min. We’ve been taught that Vit­a­min D is the “bone vit­a­min”, but it is really more of a sun hor­mone. The word “vit­a­min” means “some­thing my body needs that I can’t make, so I must get it from the food”. D hor­mone is instead, a chem­i­cal that we make on our skin from sun expo­sure. It is a hor­mone like thy­roid, estro­gen or testos­terone. Using the proper word “hor­mone” reminds us that it affects mul­ti­ple parts of the body and that it is not “extra”. It is essen­tial to every cell in the body and it is not in the food. It is sup­ple­mented in milk but as a cup of milk has only 100 IU of vit­a­min D you would have to drink 1000 cups of milk a day to keep from being D deficient…..Low D causes infer­til­ity, poly­cys­tic ovary syn­drome and endometrio­sis: There are vit­a­min D recep­tors in the ovaries, the tes­ti­cles and the fal­lop­ian tubes to help match our repro­duc­tion to the amount of food avail­able. As the D level climbs in the fall to 80 ng/ml we make higher estro­gen and testos­terone lev­els that make us want to mate. Because our human babies develop over 9 months, the baby that is con­ceived in Sep­tem­ber is born in June. This guar­an­tees that at birth the baby is in the sun mak­ing D hor­mone because there is no D in the breast milk. Low D sup­presses ovu­la­tion so that our babies will be born when mom has food. “Poly­cys­tic ovary” describes an ovary with many eggs that are all try­ing to mature at once. Each month one egg is sup­posed to fully mature; “ovu­late”, and the rest shrink down. Because ovu­la­tion is inhib­ited by the low D mes­sage, the ovaries are stuck at the stage of many eggs try­ing to ovu­late, lead­ing to abdom­i­nal pain, often accom­pa­nied by weight gain and acne (which also result from low D).Endometrio­sis results from endome­trial tis­sue going back­ward up the fal­lop­ian tube into the abdomen instead of out the cervix, (the open­ing in the uterus), dur­ing men­stru­a­tion. Because the fal­lop­ian tube is open into the abdomen, the only thing that keeps the endome­trial tis­sue head­ing out the cervix are wave like move­ments in the fal­lop­ian tube push­ing toward the uterus. There are vit­a­min D recep­tors in the fal­lop­ian tubes that influ­ence the propul­sive move­ments, pro­mot­ing or pre­vent­ing fer­til­iza­tion depend­ing on the D level. Also, once the endome­trial cells have arrived in the abdomen, where they don’t belong, the white blood cells are sup­posed to find and kill them. Because the low D also affects the func­tion of the white blood cells the proper elim­i­na­tion of the endome­trial tis­sue doesn’t occur and fixed implants of endome­trial tis­sue appear in the abdomen.


Humira and IVIg and high cytokines

From Dr. Beer’s Q&A, http://repro-med.net/info/qabeer_08-04.pdf

“the patients who have flared while they were on Humira preconception actually show better ongoing pregnancy success rates, at least that’s what we have been finding so far. The non- flaring patient averaged 71 percent ongoing pregnancy success rate after using Humira and the flaring patients averaged an 88 percent ongoing pregnancy success rate. So people, when they have these flares, feel like they are sick and they are scared and they think they are not going to succeed and the reality is that Humira is still working and, in fact, the pregnancy success rates are higher. … Now I have got to say that these patients, when they get pregnant are not flaring. Okay, this is after the flare..They have to control the flare usually with gamma globulin, IVIg. So, there is a possibility me and Dr. Beer discussed that maybe some of these patients are using more IVIG preconception. But, in any case, after the flare, when they have had a flare, it does necessarily mean that they are going to fail on Humira.”

and

“the protocol now is for patients to take the Humira for 30 days prior to the cycle of conception, 30 days during the cycle of conception and all patients would be on it for three months, if they are pregnant they will continue until a heartbeat, if they are not pregnant, I will stop after three months and now you have a four month window of opportunity where things will remain quieted down. So, I give it in no longer now other than three months of the Humira and then stop in all individuals.”

Also I am reading a paper by Winger (2009) which concludes that for Th1Th2 high cytokine gals, Humira + IVIg had a 73% improvement in live birth rate for prior IVF failers, and when you only look at women with 2+ fails, Humira+IVIg resulted in 100% pregnancy rate and 88% had live births.

In that study they said Humira therapy was 2 – 40mg injections, wait 2 weeks, then 2 more injections. Testing in 2-3 weeks, and if not improved, a second set of injections starting 3-4 weeks after the second injection. Avg embryo transfer was 2 mo after last Humira shot.

IVIg was 400mg/kg body weight at least once during the IVF cycle with additional shots during the 1st trimester as needed (shown by repeat NK assay.) Also all patients were on 20 mg lovenox and a baby aspirin daily before conception.

Citation:  Winger EE, Reed JL, Ashoush S, Ahuja S,
El-Toukhy T, Taranissi M. Treatment with
adalimumab (Humira) and intravenous
immunoglobulin improves pregnancy rates in
women undergoing IVF. Am J Reprod
Immunol 2009; 61: 113–120

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