Early Development and Reproductive Health in Later Life
One of five workshops in a conference on
Evolution and Diseases of Modern Environments
Organized by Randolph Nesse, at the Berlin Charité, October 13-14, 2009
In conjunction with The World Health Summit
Sponsored by the Volkswagen Foundation
Session leaders: Gillian Bentley and Grazyna Jasienska
In session: Gillian Bentley, Benjamin Campbell, Kathryn Clancy, Marco Del Giudice, Vivette Glover, Grazyna Jasienska, Diana Kuh, Shanthi Muttukrishna, Pablo Nepomnaschy, Alejandra Nuñez de la Mora, Janet Rich-Edwards, Norah Spears, Hamish Spencer, Beverly Strassmann, John Wiebe
Raporteurs: Kathryn Clancy and Benjamin Campbell
In evolutionary medicine so far, a lot of emphasis has been placed on understanding disease, and with the exception of cancer reproductive function is especially understudied. We want to look at the relationship between early development and adult reproduction but we have little data. Those of us in this session have an evolutionary, ecological perspective but few have also thought about a broader health perspective to combine both disciplines. Preliminary discussions identified nutritional status and psychosocial stress as crucial to this combined perspective, and could provide a direct link to evolutionary medicine.
We first sought to define “stress” and largely arrived at the idea that one way, for the purposes of this session, is to define “stress” as anything that activates the HPA/limbic system. We also tried to clarify the difference between stressors and stress, and the measurable outcomes relevant to fitness/reproductive success. We focused on the female reproductive system as an incredibly plastic system, perhaps more plastic than any other process in the body. We tried to turn towards some of the main “stages” in order to get a sense of what is already in the literature, what it tells us, how it may or may not be biased (in terms of where we focus our research attention) and where we should thus direct future research.
For the first session we focused more on age at menarche as a stage and perhaps biomarker that we could use as a way to get at 1) environmental predictors of variation, 2) variation in reproductive outcomes and 3) seemingly competing hypotheses. For instance, we have support to suggest that early psychosocial stress leads to early menarche, but also that early good nutrition leads to early menarche. However, individuals who have early menarche due to good nutrition will be larger, and thus it is less of a trade off than when early psychosocial stress drives an earlier move to reproduction. Further, this is context-specific, it’s about whether you can afford this trade-off or not.
In the second session we discussed the Predictive Adaptive Response (PAR) and other hypotheses that may explain reaction norms in reproductive physiology. Our conversation was inconclusive. In large part this was due to the fact that we were unsatisfied with the degree of evidence in the literature, particularly of a longitudinal nature, that will help us test competing hypotheses. We noted that the PAR’s emphasis is on prenatal exposure but that doesn’t mean PAR is exclusive to the prenatal period. We also noted problems in use of rodent models because they are short-lived and have different life histories – perhaps we find epigenetic/ intergenerational effects in rodents but that doesn’t mean we can find them in humans. Ultimately, long-lived species have a continuous plastic response: perhaps we can think about the fetus making the best decision it can: there is some reduction of variation after that decision, but still plasticity after fetal programming.
On the second day, we broke into small groups that focused on reproductive maturation, fertility and pregnancy as processes to put most of our attention.
In our reproductive maturation group, discussion centered on separating effects of adrenarche (onset of adrenal androgen production) and puberty. While the hormonal processes associated with these two events are clearly separate, their relationship to obesity may be coordinated. Recent work in child development has focused on the importance on the interval between adrenarche and pubarche as crucial for socialization including sexual behavior and gender roles. Thus there is an urgent need to study and understand the impact of modern environments and obesity on earlier maturation, and a possible shortening of the window between adrenarche and pubarche, on socialization, sexual behavior and gender roles. Cross-populational studies are crucial to establish baseline patterns of the relationship between adrenarche and pubarche and their importance to socialization.
In the pregnancy group, two important issues we considered were pregnancy loss and pre-eclampsia (hypertension during pregnancy) because of the ecological perspective we can offer. In addition to chromosomal abnormalities, nutritional status or psychosocial stress could impact the degree of fetal loss, and while significant work has been done on the maternal-fetal conflict in pre-eclampsia, we also want to offer the perspective that modern environments and overnutrition could provide additional important insights. We also know very little about population variation in either of these conditions, and propose future research in this direction for hypothesis testing and assessment of baseline variation.
The fertility group’s main conclusion was that we need to bring our particular approach to variability to medicine. We have discussed variability and its importance throughout this symposium but we need to better define what we mean and why we consider our approach so important to medicine. The main problem we note is that we are uncomfortable making strong recommendations to medicine regarding reproductive health because we do not yet have enough baseline data of the normal range of variation within and between women and within and between populations. The focus in funding mechanisms is on basic molecular science and disease-focused science, and our discipline falls between these two extremes. Thus we first propose a greater emphasis on research that assesses normal variation in the following ways: longitudinal, repetitive sampling, an assessment of lifestyle factors, documentation of ethnic and geographic variation, and a focus on the major lifestyle transitions as these can be periods of major variability. For instance, important transitions include cycling to pregnancy, or lactational amenorrhea to resumption of fecundity. Finally, we wanted to point out that the population that the majority of our data is western and economically developed, and that they represent the most extreme and highest concentrations of ovarian hormones (and likely other indicators of reproductive function).
One recommendation we did want to make, or at least propose as a hypothesis, is that we should reduce pharmacologic interventions in young women. In many industrialized countries the majority of young women are on hormonal contraceptives for supposedly abnormal cycling, when they are usually experiencing adolescent subfecundity. However hormonal contraceptives increase young women’s exposure to exogenous hormones and their possibly mitogenic activity in the breast and other tissues, thus possibly increasing their risk of breast cancer. This is contrasted by the possibility that this intervention is beneficial in premenopausal women with established cycling, at least in industrialized environments, because the exogenous hormones may be lower than the endogenous levels and thus, by disrupting the HPO axis, lower women’s exposure. We want to be clear that we recognize the importance of hormonal contraceptives for actual contraceptive use, but we strongly suspect its off-label use for cycle regulation far outstrip its contraceptive use in certain populations. It is for this reason that our emphasis on the exploration of normal variation is of such urgent importance. We would like to see a move towards non-pharmacologic intervention, such as intervention in lifestyle, in those situations where young women are experiencing discomfort from which they would like to be relieved. However, we also suspect that many young women who seek help for “abnormal cycling” are suffering from misinformation about what constitutes normal, and correct information about the fact that their bodies are operating well may go far in reducing their concerns.
From the perspective of evolutionary medicine the study of reproductive function is relatively undeveloped. At its current stage the most crucial tasks are to increase our knowledge of normal variation in reproductive processes, to study populations cross-culturally, and to examine lifestyle transitions and early environments as containing stages that can have a significant impact on later reproductive outcomes.
Thank you for a thoughtful work. I have a few concerns about the last paragraph, however. For one, use of birth control is not associated with breast cancer (multiple citations at NIH and CDC). Second, using hormones to regulate cycles is not “off-label”. Finally, I would question “what constitutes normal”. How many species postpone breeding until they have finished school and are stable in their career? It was probably only a few generations ago that Homo sapien couples formed in early puberty. If hormonal contraception creates an artificial pseudo-pregnancy state so the ovaries do not ovulate, possibly for many months in a row, might that not be more “normal” than doing nothing? I had a patient once who had never had a period –she had always been pregnant or nursing. It seems that her method of not having periods was quite normal. Unfortunately, contraception has always been political and controversial.
Katherine, thank you for your comments. We were suggesting — and were pretty clear, I think, to point out this is a testable hypothesis, and by no means is proven or known at this moment — that hormonal contraceptives in postmenarcheal girls is problematic. We were also very clear that in premenopausal women with established cycling we suspect hormonal contraceptives are beneficial. Our concerns are twofold: 1) are hormonal contraceptives harmful to young girls experiencing normal “irregular” cycles as a common aspect of adolescent subfecundity because they are receiving more hormone than they would if their cycles were left alone and 2) what does one “regulate” a cycle for? What does the word mean, why do we do it, why would someone want a “regulated” cycle? Is it possible, then, that our desire to “regulate” a period of time in girls during which it is normal and healthy to have “irregular” cycles causes harm in the form of additional hormone exposure? That is our question, and with luck we will have the time, the data, and the funding to answer it.