New fertility links in women identified

Significance

When a woman is born, she possesses a fixed number of oocytes, and they are lost throughout life from before birth to menopause. Women, unlike men, have a finite reproductive window that spans from sexual maturation and the first menstruation or menarche to the final menstruation and menopause. Menarche occurs about 2 years after the onset of puberty, around a mean age 12–13 years, and menopause takes place around a median age of 51 years.

Notably, many genetic studies have linked early menarche with great risk for obesity, type 2 diabetes mellitus, insulin resistance, cardiovascular disease, and various cancers including breast cancer, while later age of menarche is linked with increased risk of osteoporosis, decreased fertility, reduced risk of cardiovascular disease and diabetes mellitus, etc. The female reproductive window, reproductive aging, and fertility are also closely associated with several ovarian reserve markers, including antral follicle count (AFC), which can be measured non-invasively by transvaginal ultrasound. Antral follicle count, like menarche and menopause, is highly variable among women and has a high heritability. AFC, which is closely correlated with the total number of oocytes, can be a predictive factor for fertility loss, which occurs approximately 10 years before menopause. Interestingly, follicle number and menopausal age share several underlying genetic variants and are likely strongly genetically programmed traits. However, it is not clear whether AFC may also be correlated with the beginning of the reproductive lifespan or whether age at menarche can predict follicle/oocyte number later in life.

To this end, in a recent research paper published in the journal, Fertility and Sterility, Saint Mary’s College of California scientists: Dr. Sonya Schuh and Julia Kadie in collaboration with Drs. Mitchell Rosen and Marcelle Cedars of the University of California San Francisco, Dr. Barbara Sternfeld of Kaiser Permanente, and Dr. Renee Reijo Pera of Montana State University, examined the relationship between the age at menarche, antral follicle count, and body mass index (BMI) in a multi-ethnic population of women (443 African American and European American women between the ages of 25 and 45 years, with regular cycles and no reproductive disorders).

This study discovered new associations between age of menarche, body mass, and antral follicle count. Age of menarche was negatively associated BMI, with earlier menarche associated with greater BMI levels. Further, in the European American women, those who fell in the obese BMI range, had a greater number of antral follicles, but these follicles tended to be smaller in size. However, in the African American women, higher BMIs were associated with lower mean follicle counts. Also, there was a significant difference between the normal weight women and obese women, with the normal weight women having higher mean AFCs. Furthermore, the authors observed that AFC was negatively associated with age in both ethnic groups (showing the loss in follicles throughout adult life) and BMI was found to be significantly associated with amount of African ancestry; meaning individuals with greater African ancestry had significantly higher BMIs.

Most interestingly however, this study by Professor Schuh and colleagues showed that the timing of menarche in adolescence may influence both adult BMI and antral follicle count among white and black women. As menarcheal age went up, average follicle count went down. This relationship crossed ethnic backgrounds, as it was present in both white and black women. Specifically, earlier age of menarche was associated with higher antral follicle counts (11–13% increase), while later age of menarche was associated with reduced follicle counts (8–13% reduction). In this significant association, the average antral follicle difference between early vs. late initiation of menarche (<11/12 vs. >15 years) was equivalent to an approximate 20% difference in AFC.

The connection between BMI and menarche is similar to many previous findings of higher body fat and BMI in females who experienced an earlier age of menarche and were “early bloomers.” Excitingly, this study also finds a new connection between menarche and follicle (oocyte) number. Schuh states, “This new finding represents new fertility links we were never aware of, and may help explain why women with later ages of menarche have been reported to have overall slightly reduced fertility, while those with earlier ages of menarche tend to have increased fertility. Before our study, we never really knew why that would be the case.” Earlier work analyzing follicle numbers from ovarian biopsies have found that the total number of follicles are depleted throughout life until there is around 1,000, at the time of menopause. The greatest losses of follicles seem to occur during the early adolescent years (10–19 years) and in mid-life (35–40 years). The authors hypothesize that menarche and ovarian cycling may slow this follicle loss. Therefore, girls who begin cycling sooner might avoid the bigger follicle loss that happens in the early teenage years.

This work provides new associations between ovarian reserve and age of menarche in a multi-ethnic, normative population of women, and also provides additional important data on African American women, owing to women of non-European ancestry being understudied and underrepresented. Indeed, such studies like this can provide a better understanding of the phenotypic/genotypic variation and how it correlates with the female reproductive lifespan. “The ultimate goals are to enhance our ability to prospectively screen women, assess disease risk, and better treat various diseases associated with the reproductive lifespan such as infertility and breast cancer. Our next steps are to closely examine the underlying genetic links that may help explain some of these new associations,” says Schuh.

New fertility links in women identified - Medicine Innovates
The development and depletion of the human female oocyte pool and associated reproductive lifespan showing relationships between menarche, menopause, and antral follicle count. This work demonstrates new potential links between age of menarche, body mass, and antral follicle count (red arrow), finding that earlier age of menarche is associated with both higher antral follicle counts and higher body mass, while later age of menarche is associated with reduced follicle counts and lower body mass (modified from Schuh et al. 2019).

New fertility links in women identified - Medicine Innovates

About the author

Dr. Sonya Schuh, Ph.D., is an Assistant Professor in the Department of Biology at Saint Mary’s College of California, in Moraga, of Northern California. Her research is focused on the genetic and environmental factors of fertility, the effects of various environmental toxins on embryo and stem cell development, and cancer-causing and chemotherapeutic agents.

The overall objective of her work is to uncover many of the genetic and environmental correlates of fertility and development, from frogs to humans, with implications for human reproductive health and treatment of disease. Dr. Schuh completed her Ph.D. in Physiology and Biophysics at the University of Washington, in Seattle, under the mentorship of Drs. Bertil Hille and Donner Babcock, where she investigated the effects and underlying signaling pathways of various compounds on mammalian sperm motility, capacitation, and fertilization. She went on to a postdoctoral fellowship at Stanford University, at the Institute for Stem Cell Biology and Regenerative Medicine, under the guidance of Dr. Renee Reijo Pera. At Stanford, she switched gears and focused on female reproductive health, the genetics of fertility, and critical genes and pathways of stem cells and embryos. Dr. Schuh began her faculty position at Saint Mary’s in 2013, where balancing teaching, research and service has been her focus. She has maintained a vibrant year-round research program where she has trained numerous undergraduate students, many of whom have been first-generation and/or underprivileged college students, who have presented their research at professional national meetings, won awards, co-authored publications with Dr. Schuh, and gained acceptance into graduate, clinical, and professional programs. Professor Schuh currently has several publications in press, which include mostly undergraduate student co-authors. Her research, teaching and service all have a strong focus on supporting the success, solidarity, and health of women.

Professor Schuh regularly teaches several popular, challenging courses including: Human Anatomy, Human Physiology, Cell and Molecular Biology, Stem Cell Biology, Women’s Biology, and the Biology of Sex, Love, and Attraction. Dr. Schuh is also the creator and academic advisor of the Saint Mary’s Women in Science and Engineering (WiSE) student organization. She is also a proud, single mother of three children, and is an artist, animal lover, dancer, former triathlete, and enjoys the ocean, including conducting marine ecology studies on endangered sea turtles, during her ‘free time.’

Reference

Schuh, S., M., Kadle, J., Rosen, M., P., Sternfeld, Reijo-Pera, R., A Links between age at menarche, antral follicle count, and body mass index in African American and European American women. Fertility and Sterility. Vol. 111, No. 1, January 2019 0015-0282.

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