April 27, 2019 | Vol. 5
Distributed by the International Institute for Restorative Reproductive Medicine
Want to share your thoughts or have a paper you want discussed?
Polycystic Ovarian Syndrome and Autoimmune thyroid disease:
 a systematic review and meta-analysis.
This is a very interesting article that explores the evidence for a relationship between PCOS (Polycystic Ovarian Syndrome) and autoimmune thyroid disease (AITD). PCOS is a complex endocrinopathy that is the most common hormonal abnormality in women. AITD is often attributed as the most frequent factor causing hypothyroidism in young women, and is noted to be present in 18 -40% of PCOS women. 

The authors identified 811 original research articles in their primary literature search. Of those, 13 studies were included in the final analysis, which used systematic review and meta-analysis. 1210 women with PCOS and 987 healthy controls made up the meta-analysis, which utilized the Newcastle–Ottawa Scale (NOS) 2 to assess the quality of the included studies based on three factors: study group selection, group comparabilitky and determination of defined outcome.  The PICOS approach was used in the design of this study:

Population: Women in the menacme
Intervention: Diagnosis of PCOS using Rotterdam Criteria
Comparison group: Women without PCOS
Outcome: Auto-immune thyroid disease (AITD)
Study Design: included non-interventional case control, cohort and cross-sectional studies

What did they find?

“Overall, a significant association was observed between PCOS and the presence of AITD (OR?=?3.27, 95% CI 2.32–4.63; P?<?0.0001). After geographical stratification, the higher chance of AITD in PCOS persisted for Asians (OR?=?4.56, 95% CI 2.47–8.43), Europeans (OR?=?3.27, 95% CI 2.07–5.15) and South Americans (OR?=?1.86, 95% CI 1.05–3.29); however, the difference between subgroups was not statistically significant (P?=?0.0987).” 3 So there does appear to be an increased risk between women with PCOS and the chance of developing auto-immune thyroid disease. Why and what could that relationship be?

PCOS is known to be an inflammatory condition. Anovulation or oligoanovulation are common in PCOS with low post-peak progesterone levels and estrogen dominance, resulting in a high ratio of estrogen to progesterone. This excess estrogen is believed to increase the risk of autoimmune disorders through the unopposed stimulator effect of estrogen on the immune system 4. Other features of PCOS also impact immune functioning: excess androgens enhance T suppressor cell activity, promoting TH1activation of CD8C and progesterone levels altering macrophage production, IL6 and antibody production 5.

AITD is thought to be an immune attack resulting in chronic inflammation in the thyroid and often shows positive thyroid antibodies (TPOAbs and/or thyroglobulin (TgAbs) long before clinical symptoms are present 6. A 2017 systematic review found that subclinical hypothyroidism in PCOS patients was associated with an increase in mild metabolic abnormalities including changes in HOMA-IR (insulin resistance) and lipid abnormalities 7.

The authors of this paper suggest that PCOS patients should be screened for subclinical thyroid abnormalities and thyroid antibodies. Does this fit with your experience in RRM? Do you screen your PCOS patients for thyroid abnormalities? If not, will you start? Why or why not?
(1) Romitti, M., Fabris, V. C., Ziegelmann, P. K., Maia, A. L., & Spritzer, P. M. (2018). Association between PCOS and autoimmune thyroid disease: a systematic review and meta-analysis. Endocrine connections, 7(11), 1158–1167. doi:10.1530/EC-18-0309
(3) Janssen OE, Mehlmauer N, Hahn S, Offner AH, Gartner R. 2004. High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome. European Journal of Endocrinology  
(4) Petrikova J, Lazurova I, Yehuda S. 2010. Polycystic ovary syndrome and autoimmunity. European Journal of Internal Medicine. 21 369–371. (10.1016/j.ejim.2010.06.008)
(5) Hughes G. C. (2011). Progesterone and autoimmune disease. Autoimmunity reviews, 11(6-7), A502–A514. doi:10.1016/j.autrev.2011.12.003 
(6) Dayan CM, Daniels GH. 1996. Chronic autoimmune thyroiditis. New England Journal of Medicine. 
(7) Pergialiotis V et al. 2017. Management of Endocrine Disease: the impact of subclinical hypothyroidism on anthropometric characteristics, lipid, glucose and hormonal profile of PCOS patients: a systematic review and meta-analysis. European Journal of Endocrinology.

Natural Killer cell activity in women with recurrent miscarriage:
Etiology and pregnancy outcome. 

Recurrent miscarriage (RM), defined as two or more consecutive losses of clinical pregnancy, affects about 1-2% of women. Etiologies can include uterine abnormalities, antiphospholipid antibody, chromosomal abnormalities, thrombophilic disorders, infections, autoimmune disease, and endocrine disorders. However, about 50% of RM have unknown etiology, and immunological abnormalities are presumed to play a large role. Although there is controversy over the role of natural killer cells (NK) in infertility and RM, a recent systematic review showed the number of peripheral NK in infertile women was higher than fertile controls (Seshadri and Sunkara, 2014). The predictive power of NK cells toward pregnancy outcomes is unknown. This study aimed to evaluate if peripheral NK cell activity is associated with risk factors of RM, and if they are predictive of outcomes of subsequent pregnancies. 

This was a prospective cohort study, enrolling 160 women with RMs. Women had ultrasound, endometrial biopsy and extensive labs. They were considered to have known risk factors/etiologies of RM if they were found to have a uterine abnormality, thyroid dysfunction, chromosomal abnormality, antiphospholipid syndrome, PCOS, hyperprolactinemia, autoimmune diseases, protein S or C deficiency, or low factor XII. 
Peripheral NK cell activity was measured once in the luteal phase, and then compared between women with RM and a known risk factor/etiology and those without identified risk factors/etiologies. NK cell activity was compared in those women who had a subsequent pregnancy, and those that didn’t by end of study, as well as according to pregnancy outcomes.
95 women had one or more risk factors, and 65 had no identified risks. The most common identified risks were antiphosphatidylethanolamine IgM (25), high ANA, or thyroid dysfunction. 

The NK cell activity was statistically higher in women with no identified risk factors compared to women with any risk factor.(p<0.001) Women who subsequently become pregnant had a lower NK cell activity compared to those who didn’t become pregnant but P=0.065. 

Of those that become pregnant, the NK cell activity was higher in those with miscarriage with normal chromosomes ( n=17) compared to live births(n=68)(p<0.5)or miscarriage with abnormal chromosomes(n=9). 

High NK cell activity(>/ 33%) was indicative of a 2.7 fold greater risk of miscarriage with normal chromosome karyotype or biochemical pregnancy compared to low levels. The authors suggest that the higher NK cell activity is causally associated with unexplained RM with normal chromosomal karyotype and might be involved in the pathophysiology. This information may be beneficial for selecting therapeutic options for women with high NK cell activity. They mention the study by Morikawa, 2011 that showed a high dose of immunoglobulin in early pregnancy suppressed peripheral NK cell activity, although administration has been controversial. 

Peripheral NK cell activity can be affected by exercise, infection, and stress, but the NK cell activity was only measured once in this study. How do you think RRM could use this knowledge? Is NK cell activity something you check in your patients with recurrent miscarriage, or is it something you would consider in the future? Share your thoughts to the forum!
(2) M. Morikawa, H. Yamada, E.H. Kato, S. Shimada, T. Kishi, T.Yamada, et al.Massive intravenous immunoglobulin treatment in women with four or more recurrent spontaneous abortions of unexplained etiology: down-regulation of NK cell activity and subsets
Am. J. Reprod. Immunol., 46 (2001), pp. 399-404
(3) S. Seshadri, S.K. SunkaraNatural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis
Hum. Reprod. Update, 20 (2014), pp. 429-438
Cannabis Use Increasing in Women of Childbearing Years

Cannabis and synthetic cannabinoids are common drugs of abuse, and with increased legalization in recent years, there is an increase in the exposure to these drugs. Cannabis appears to be increasing in women of childbearing years and based on a study by NIDA (National Institute on Drug Abuse) 1 the self-reported cannabis use during pregnancy was 2.9%. With the legalization of medical and recreational cannabis in several states and Canada, the use in pregnancy is expected to increase due to the perception that cannabis may be less harmful to the developing embryo than other drugs. However, evidence is increasing that cannabis exposure during pregnancy may significantly impact fetal brain development causing hyperactivity, poor cognitive function and neurological impairments. Regular use of cannabis in pregnancy has been associated with lower birth weight, and after adjusting for tobacco and other illicit drug use, cannabis was associated with increased neonatal morbidity or death. 

Endogenous endocannabinoids, along with the receptors and associated metabolic enzymes form the endocannabinoid system (ECS). The ECS is involved in fertilization, oviduct transport, implantation and embryo development. One of the major endocannabinoids is anandamide (AEA), which shows downregulation and lowest levels at the site of implantation. Interestingly, progesterone promotes the lowering of the AEA. Elevated levels of AEA are associated with decreased implantation. THC is metabolized slower than the endogenous cannabinoids and may have potential negative impacts on fertility. 

In addition to impaired fertility, THC crosses the placenta, and in mice has shown effects on the immune system of the mice offspring after delivery, with thymic and splenic decreased cellularity. It is suspected that the fetal immune system can be altered with exposure in-utero, with long lasting effects on the ability to fight infection and cancer. Maternal cannabis use and incidence of childhood malignancies has been studied, and an association has been found between cannabis use in pregnancy and childhood acute non-lymphoblastic leukemia, and neuroblastoma, if used in the first trimester. 
If you are interested in the theories for the pathophysiology, they have given an intriguing discussion. 

The recent legalization of cannabis and synthetic cannabinoids in Canada, Uruguay, and several US states, has made increasing legal use among the general population a reality. Is this something you consider when completing intake on a patient of childbearing years? Do you currently screen for cannabis use a as regular part of your intake process? Will you be doing this in the future?

Dong, C., Chen, J., Harrington, A. et al. Cell. Mol. Life Sci. Cannabinoid exposure during pregnancy and its impact on immune function. (2019) 76: 729. https://doi.org/10.1007/s00018-018-2955-0
In partnership with the Clínica Universidad de los Andes and our Latin American and Spanish Colleagues, IIRRM is excited to be able to offer virtual attendance to the 3 day Latin American Conference for RRM, Fertility Centred on the Person ( Jornadas latinoamericanas regionales de medicina reproductiva restaurativa)  being held in Santiago, Chile May 2-4. 

Approved for Continuing medical education credits*, this conference will bring together health care professionals worldwide, offering professional development, education, and networking among a range of health care providers and researchers who are seeking to improve reproductive treatment and care provided to both men and women in the area of reproductive medicine. 

Registration is $100 for IIRRM members ($125 for non-members) and $50 for IIRRM member students ($60 for non-member students). English and Spanish translation will be offered throughout the conference, and all webinar attendees also receive complementary access to recordings and slides from the lectures posted to the IIRRM website following the conference.

*This Live activity, The Latin American Regional Conference for Restorative Reproductive Medicine, with a beginning date of 05/02/2019, has been reviewed and is acceptable for up to 16.50 Prescribed credit(s) by the American Academy of Family Physicians. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Don't Miss this chance and attend Virtually!

Invited Speakers:

  • Prof. Antonio Amado, U de los Andes, Chile
  • Dr. José Antonio Arraztoa, U de los Andes, Chile
  • Dra. Helvia Temprano, RENAFER, La Coruña, España
  • Dra. Gloria Sánchez, U Austral, Argentina
  • Dra. María Elena Alliende, U de los Andes, Chile
  • Dr. Roberto Angioli
  • Dr. Francesco Plotti
  • Sra. Pilar Gil, U de los Andes, Chile
  • Sra. Carolina Brañas, U de los Andes, Chile
  • Matrona Ximena Mallea, U de los Andes, Chile
  • Matrona María Teresa Gana, U de los Andes, Chile
  • Dr. Joseph Stanford, IIRRM, USA
  • Dr. Alejandro Serani, U San Sebastián, Chile
  • Dr. Alvaro Ruiz, U Navarra, España
  • Dr. Luis Chiva, U Navarra, España
  • Dr. Manuel Donoso U de los Andes, Chile
  • Dra. María Lombarte, U Navarra, España
  • Dr. Martín Ballarin, U Austral, Argentina
  • Dra. Tania Errasti, U Navarra, España
  • Dr. Raúl Sánchez, U de la Frontera, Chile
  • Dr. Ignacio Morales, U de los Andes, Chile
Can't decide which one to attend?
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Register for CyclePower Summit &
get 15% off Santiago!

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Conference Registration includes immediate access to slides and recordings of all conference proceedings posted to the IIRRM website shortly after the conference.
IIRRM is proud to sponsor an exciting initiative and invites all members to join and help spread awareness of this event :
Introducing 4 days of 30+ dynamic sessions with leaders in the field of fertility awareness and women's health, 100% free and virtual May 2-5, 2019.

Who it's for ....

-- Medical professionals who want to connect with other restorative-minded clinicians and educators and learn the latest happenings in fertility awareness programs.
-- Women and couples who want to learn how to manage their fertility and health through the power of their menstrual cycle.
-- FABM educators who want to learn more about the latest happenings in the industry.

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Register before May 1st!
Join us in Blue Bell, PA, USA July 17, 2019 for a packed day with speakers, abstract presenters and a panel discussion at North America's Regional Conference for Restorative Reproductive Medicine. 

Presenting Speakers:

Sunni Mumford, PhD 
Eric Chang, DO
April Lind, MD
Kim Bigelow, MD
Eddie Fleming, MD 
Joe Stanford, MD
Marguerite Duane, MD

Physician Panel on Directed Patient Care, moderated by Eddie Fleming, MD

Just one month left to submit your abstract for presentation at the IIRRM's 16th Annual General Meeting and Scientific Assembly, taking place 7 September, 2019 in Dublin, Ireland .

Abstracts are welcome in any area relevant to Restorative Reproductive Medicine. RRM seeks to understand, restore, and support the natural processes of human reproduction and excludes interventions that suppress, destroy, or circumvent natural human reproduction. View full guidelines and submission information on our website.

This years conference will be held at :

Crowne Plaza - Dublin Airport
Northwood Ave, Santry, Dublin, Ireland

Explore more conference information at

Abstract Submission for presentation at IIRRM's International Scientific Assembly and AGM close May 29, 2019.

Disclaimer:  The material presented in the Bulletin or Journal Nook are for educational purposes only. Please note that medical information is constantly changing; the information contained in this activity was accurate at the time of publication. This material is not intended to represent the only, nor necessarily best, methods or procedures appropriate for the medical situations discussed. Rather, it is intended to present an approach, view, statement, or opinion of the Author or Institute, which may be helpful to others who face similar situations.

RRM providers often use fertility awareness-based methods to help patients. The IIRRM does not endorse one method over another but supports the use of all validated science-based fertility models. Most commonly recognized methods include Billings, Creighton, FEMM, Marquette, Neo, SymptoThermal and other mucus sign-based methods. It recommends caution to patients when using simple, unproven or proprietary fertility apps and strongly encourages patients to consult an RRM professional when deciding on the best method for their personal situation.

Restorative Reproductive Medicine (RRM) does NOT use methods that are inherently suppressive, circumventive or destructive, such as ART techniques including IVF, AI, ICSI and others. However, research involving these approaches can sometimes be modified and applied in a restorative manner and is thus reviewed here with that intent. The IIRRM does not use or condone ART or any non-RRM techniques.