March 29, 2019 | Vol. 4
Distributed by the International Institute for Restorative Reproductive Medicine
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Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Two of the most common medications to induce ovulation in PCOS are clomiphene citrate ( CC) and letrozole. The Pregnancy and Polycystic Ovary Syndrome trial showed that letrozole had a higher live birth rate (27.5% vs. 19.1%, p=.007) and cumulative ovulation rate ( 61.7% vs 48.3%, P<.001). 

CC works as a selective estrogen receptor modulator, attaching to nuclear estrogen receptors. With the reduction of negative feedback from estrogen, gonadotropin hormones increase, causing growth of the ovarian follicle. Despite higher ovulation rates, CC has been associated with low pregnancy rates, possibly due to the antiestrogenic effect on the endometrium and cervical mucus. 

Letrozole is a highly selective aromatase inhibitor, which prevents androgen to estrogen conversion. Decreased estrogen production leads to decreased negative estrogenic feedback and increased FSH. The temporarily increased introavarian androgens may make the follicle more sensitive to the FSH, with improved ovulation. Letrozole does not block estrogen receptors, so the central feedback mechanisms remain intact. 

Because of the different mechanisms, it was postulated that a combination of CC and letrozole would improve ovulation better than letrozole alone. A randomized controlled trial was performed on women aged 18-40 with PCOS and infertility, with 35 women in the letrozole only group and 35 treated with letrozole and CC. Letrozole 2.5 mg was given daily, and the combination group also had CC 50 mg daily, on cycle days 3-7. Participants used ovulation prediction kits, and had mid-cycle ultrasounds, coupled with progesterone and pregnancy testing. 

With intention-to-treat analysis, ovulation occurred in 42.95% of women on letrozole alone, and in 77.1% of the combination group. Conception and pregnancy were similar in both groups, but too few to be statistically significant. Side effects were somewhat higher in the combination group but nearly all of them felt it wasn’t bad enough to stop them from trying the regimen again. Some women were on metformin, but similar numbers in each arm. 

The authors concluded that the combination of letrozole and CC is superior to letrozole alone, and offers a low risk, low cost treatment compared to gonadotropin injections. 

As RRM providers, what do you think? Have you tried the combination? Share your thoughts on the forum. 
Mejia, Rachel B. et al. "A randomized controlled trial of combination letrozole and clomiphene citrate or letrozole alone for ovulation induction in women with polycystic ovary syndrome."  Fertility and Sterility , Volume 111 , Issue 3 , 571 - 578.e1 https://doi.org/10.1016/j.fertnstert.2018.11.030

Obstructive sleep apnea (OSA) is very prevalent in women with PCOS. Both OSA and PCOS have been linked to insulin resistance, oxidative stress and abnormal gonadotropin releasing hormone (GnRH), which raises the question of whether the combination of the disorders together leads to more severe forms of PCOS and worse long term consequences. This systematic review examined the effect of OSA on clinical and metabolic factors in women with PCOS by looking at studies that compared the variables in a group of women with PCOS with or without OSA.

Women with both PCOS and OSA had higher BMI, waist circumferences, and waist to hip ratios compared to PCOS alone. Systolic and diastolic blood pressures were higher in the women with both disorders by 10.8 mmHg and 4.63 mm Hg, respectively. Hirsutism was higher in the combined group. Unfortunately, none of the studies reported differences in fertility. Testosterone levels were not significantly different. 

The combined group had significantly higher fasting plasma glucose, 2 hr plasma glucose on OGTT, HOMA-IR and fasting plasma insulin levels. They also had higher total cholesterol and LDL, but lower HDL. 

In conclusion, OSA is associated with worse clinical and metabolic profiles in women with PCOS. It is unclear if this is independent of obesity, but treatment of OSA has been shown to reduce insulin resistance, blood pressure and norepinephrine levels in women with PCOS and may provide an additional treatment modality to mitigate the increased risk of diabetes, cardiovascular disease and hypertension. Studies comparing changes in menstrual cycles and fertility outcomes between those women with PCOS and OSA vs only PCOS are needed, as well as studies which examine the impact CPAP can have on reproductive health. 

Do you ask your women with PCOS if they snore or feel tired? Perhaps putting the questions into your EMR template for PCO may help us gather more data. Would love to hear what people are doing in their practice? is it routing yet to screen for OSA?
Kahal H, Kyrou I, Uthman O, Brown A, Johnson S, Wall P, Metcalfe A, Tahrani AA, Randeva HS. The association between obstructive sleep apnoea and metabolic abnormalities in women with polycystic ovary syndrome: a systematic review and meta-analysis. Sleep 2018. 41 1–12. ( 10.1093/sleep/zsy085 )
Few studies to date have focused on whether residential proximity to high voltage power lines could be associated with the increased risk of female infertility. In this recent case-controlled study, 462 women with a confirmed diagnosis of unexplained infertility, or women where infertility could be attributed to behavioural and/or environmental factors were compared with a control group of 471 persons with no history of infertility. The studied women were divided into three groups based on their proximity of residence to high voltage power lines. The mean age of the participants was 27.7 with most (66.1%) participants aged between 16 and 29 years.

The researchers found that those women who lived near power lines were more likely to have infertility--of the population surveyed in the study, those residing within 500m of the power lines were about four times more likely (aOR 4.44, 95% CI 2.77 to 7.11) to suffer from infertility than those that were over 1000m away. This is particularly relevant as the authors concluded that current safety guidelines suggested for power line safety were not enough and needed revision. Additional research is still needed to address the limitations in this study, such as potential exposure measurement errors (findings in this study were based off actual distance from the power lines instead of a direct measurement of the electromagnetic field strength with a low-frequency gauss meter).

Power line EMF is classified as extremely low frequency radiation and there has been both concern and debate over power line radiation and its effects on human health over the last 50 years. Hundreds of papers and studies have been written and performed looking for associations between this type of radiation and harmful biological effects. Early papers showed an increased risk of leukemia and other cancers, while later studies have suggested an increased risk of miscarriage, birth defects and reproductive problems. However, while some of these studies reported a negative biological association others did not, the inability to recreate original results from previous studies leaves scientists unable to come to specific conclusions for the general population. In addition there may be factors such as population bias that can be difficult to control for in some studies. High voltage power lines can decrease property values of the properties they run through, suggesting individuals with lower incomes, which are already known to have an increased risk of poor health and can lack access to basic healthcare services, may be more likely to reside in these areas.

While some research on ill health effects from EMF remains inconclusive, and we don't fully understand exactly how EMF radiation appears to affect human health, is this something you consider when a patient presents with infertility? Have you ever screened for proximity to high voltage power lines either currently or for an extended period of time in the past? Share your thoughts on this in the Forum.
Image Source: Electric and magnetic fields and health . http://www.emfs.info/

Esmailzadeh S, Delavar MA, Aleyassin A,  et al.  Exposure to electromagnetic fields of high voltage overhead power lines and female infertility.  Int J Occup Environ Med  2019;1:11-16. doi:   10.15171/ijoem.2019.1429
Last Call for Abstracts !
Abstract submission for the North American Regional Conference being held in BlueBell, PA close in 3 days!

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.

This year's conference is located at:

Normandy Farm Hotel and Conference Centre 
1402 Morris Rd.
Blue Bell, Pennsylvania, USA
19422

Abstract submissions are also now being accepted for the IIRRM's 16th Annual General Meeting and Scientific Assembly, taking place 7 September, 2019 in Dublin, Ireland .
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. 

Register early to take advantage of our early bird rates, valid until May 1, 2019. 

Presenting Speakers:

Sunni Mumford, PhD 
Eric Chang, DO
April Lind, MD
Kim Bigelow, MD
Eddie Fleming, MD 
Joe Stanford, MD
Physician Panel on DPC, moderated by Eddie Fleming, MD

Announcing a Three Day RRM Conference in Santiago, Chile!

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. 

This conference brings together health care providers and researchers from across the globe, seeking to improve reproductive treatment for both women and men, with a patient centred and restorative approach.

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.

* Application for CME credit has been filed with the American Academy of Family Physicians. Determination of credit is pending.

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
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.

Join the conversation @cyclepowersummit
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, 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.