1 Institute for Primary and Preventative Health Care, and Department of Anthropology, Binghamton University (SUNY), Binghamton, NY 13901, USA, 2 Department of Anthropology, University College London, Gower Street, London WC1E 6BT, UK, 3 Department of Bioenergetics, Instituto Boliviano de Biología de Altura, La Paz, Bolivia, 4 Max-Planck-Institut für Gravitationsphysik, Albert-Einstein-Institut, Am Mühlenberg 1, D-14476 Golm, Germany, 5 Computer Services, Binghamton University (SUNY), Binghamton, NY 13901, USA, 6 Centre for Applied Medical Statistics, Department of Public Health and Primary Care, University of Cambridge, Institute of Public Health, Robinson Way, Cambridge CB2 2SR, UK and 7 Department of Obstetrics and Gynecology, Northwestern University Medical School, Chicago, IL 60611, USA
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Abstract |
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Key words: anthropometrics/cancer risk/ovulation/reproductive ecology/salivary progesterone
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Introduction |
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In addition, outside the USA, these studies of salivary progesterone have been restricted to relatively homogeneous rural populations. It is not known if urban dwellers in less-developed countries also have relatively lower progesterone nor is it known if the socioeconomic heterogeneity that typifies urban areas is associated with variation in ovarian function. Worldwide rapid growth of urban areas, often disproportionately among the impoverished, and the accompanying changes in lifestyle that impact health, well being and reproductive patterns, warrant a better-informed understanding of interand intrapopulational variation in women's reproductive physiology.
This study tests the hypotheses that progesterone levels are lower in Bolivian than US urban-dwelling women and that, among the former, progesterone and the rate of ovulation are lower in poorer than in better-off women. These predictions derive from empirical, albeit flawed, data suggesting lower progesterone in rural Bolivian Quechua women (Table I) and a theoretical model that posits adaptive responses in reproductive functioning to environmental stressors (Vitzthum, 1990
, 1997
, 2001
). Through strict adherence to exclusion criteria, the study design eliminates or substantially mitigates the methodological limitations noted above.
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Materials and methods |
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For two complete consecutive cycles, serial 5 ml saliva samples were collected every other day according to an established protocol (Vitzthum et al., 1993) and assayed at Northwestern University for progesterone following published methods (Lu et al., 1999
). Because salivary progesterone is stable for extended periods, samples collected under field conditions yield accurate values (Lipson and Ellison, 1989
). All Bolivian samples had comparable collection, handling, storage, and assay conditions. Coinciding with mid-follicular (days 79) and mid-luteal (days 2123) phases, standard anthropometrics (Lohman et al., 1988
) were collected by a single observer (Spielvogel). Indices included body mass index (BMI, kg/m2), total upper arm area, upper arm muscle area, upper arm fat area, and arm fat index (Gurney and Jellife, 1973
).
For comparison, a sample of Chicago women attempting to conceive provided daily salivary samples assayed for progesterone in the same laboratory according to identical protocols; recruitment details and sample characteristics have been published (Lu et al., 1999).
Data analyses
Progesterone indices
Serial progesterone values were aligned on the first day of the subsequent cycle, and the luteal phase was taken to begin at day 14. Given any span of days from x to y, we defined mean progesterone as ( of P from x to y)/(y x) where P at any time is defined by linear interpolation of the observed progesterone values, the first observation of the subsequent cycle serving as an `anchor' [a reference (fiducial) day of 0] for interpolation between the current cycle's final observation and cycle completion. This approach estimates progesterone indices at individual and sample levels, thus affording investigation of the causes of individual hormonal variation.
Ascribing ovulation
Although a luteal rise in progesterone is characteristic of normal ovulation, there is no definitive threshold of salivary progesterone below which ovulation can be said not to have occurred (Ellison, 1988). One algorithm (Ellison, 1988
; Panter-Brick et al., 1993
) infers ovulation when at least one observed luteal progesterone value is >2 SD above the mean-follicular-P levels (i.e. there is <5% probability that a given luteal progesterone value falls within the distribution of follicular progesterone). However, for a given cycle, the chance probability of observing one luteal value above this threshold rises with the number of luteal observations. Even without a systematic rise in progesterone due to ovulation, this chance probability is 0.51 (= 1 0.9514) in daily sampling (luteal observations = 14) and 0.30 (= 1 0.957) in every-other-day sampling (the typical protocol in samples from non-industrialized populations). Hence, the comparison of ovulatory rates in samples having different sampling regimes is biased by chance alone, and the comparison of those having identical sampling regimes entails a large probability that anovulatory cycles will be misclassified as ovulatory.
Because each progesterone index has a continuous distribution, any threshold used to distinguish ovulatory cycles is somewhat arbitrary. With this caveat, we have ascribed ovulation to any cycle having a mean-peak-P >110 pmol/l. To determine this cut-off, each cycle's profile (without regard to the sample from which it was drawn) was visually inspected for an apparent luteal rise in progesterone relative to the previous follicular phase, and if this rise was absent the cycle was designated anovulatory. The distribution of mean-peak-P was then examined to ascertain that cut-off value between visually designated ovulatory and anovulatory cycles that reflected a reasonable compromise between the probabilities of Type I and Type II errors (i.e. false positives versus false negatives). At mean-peak-P = 110 pmol/l, all visually designated anovulatory cycles were still classified as anovulatory, and only three visually designated ovulatory cycles were reclassified as anovulatory. This procedure has the benefit of being replicable as well as internally consistent for the samples compared in this study. In addition, the magnitude of difference in ovulatory rates between Bol-p and Bol-b (see Results) is so large as to suggest that whatever misclassification may have occurred, its effect is not substantial in this study.
Principal components analyses
No single anthropometric variable can adequately convey the extent of variation in body shape and fat deposition patterns, nor can one progesterone index adequately express the totality of progesterone levels throughout the cycle. Principal components analysis (PCA) is used here to extract those main components of body-size and composition reflected in the anthropometrics, and those features of the progesterone profile represented by the progesterone indices. These principal components (factors) are included in correlation analyses evaluating the relationships between progesterone levels and body-size and composition.
Analytical samples
Consistent with the exclusion criteria, observed cycles of <25 days or >35 days were omitted from analyses, yielding 29 Bol-p, 26 Bol-b and 22 Chicago women having at least one observed cycle length of 2535 days, inclusive. The mode number of cycles/woman was 2 in the Bolivian samples and 1 in Chicago (with a range of 14). To construct a sample of independent data points, each woman contributed a single `representative cycle' (i.e. a woman's average index for her cycles meeting inclusion criteria). Samples comprised (i) cycles without regard to ascribed ovulation status; and (ii) only ovulatory cycles. One woman from Bol-b was excluded from all analyses because her progesterone profiles strongly suggested a conception, followed by fetal loss and a non-ovulatory segment before the resumption of normal menses.
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Results |
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With these caveats in mind, for samples comprising only each woman's first observed cycle, anovulatory rate is defined as the proportion of cycles having mean-peak-P <110 pmol/l. Anovulatory rates did not differ (2 = 0.104, two-sided P = not significant) between Chicago (2/22 = 9%) and Bol-b (3/25 = 12%) but were significantly higher (
2 = 10.97, P = 0.001) in Bol-p (16/29 = 55%) than Bol-b.
Progesterone levels
Table IV (top panel) compares progesterone indices for the samples comprising all representative cycles. Peak-day did not differ significantly between the samples. Mean-luteal-P and mean-peak-P each varied significantly, being greatest for Chicago (227 and 311 pmol/l respectively) and lowest in the Bol-p (92 and 132 pmol/l respectively), Bol-b falling midway (162 and 223 pmol/l respectively). The same pattern was observed for mean-follicular-P, although Chicago and Bol-b were not significantly different.
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Figure 1 summarizes these findings. The Bol-p profile for all cycles was exceedingly low with a peak progesterone that barely rose above the anovulatory cut-off of 110 pmol/l. Removing the anovulatory cycles, represented by the virtually flat profile, revealed a profile for Bol-p ovulatory cycles much closer to that of Bol-b. Both Bolivia samples of ovulatory cycles were substantially lower than ovulatory cycles in Chicago women during the follicular as well as luteal phase of the cycle.
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Correlations of progesterone level in ovulatory cycles with body-size and composition
The analytical sample for PCA (Table V) comprises representative ovulatory cycles from all the Bolivian women (n = 40). For the anthropometrics, two factors having eigenvalues >1.0 were extracted. The first, accounting for 60% of the total variance, loaded heavily on all skinfolds as well as weight and thus represented variation in overall body-fatness (names of factors are hyphenated throughout). The second factor, accounting for 16% of the total variance, loaded principally on height and represented variation in overall body-size. For the progesterone indices, representing hormone levels at different parts of the ovarian cycle, it is as expected, that PCA extracted a single factor that represented variation in overall progesterone level (subsequently called `P-level') and accounted for 73% of the total variance. It is noteworthy that the factor loaded strongly on mean-follicular-P albeit to a lesser extent than on the luteal indices.
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No single progesterone index was significantly correlated with any single anthropometric variable, nor with BMI, except for a positive correlation between mean-luteal-P and height (r = 0.35, P = 0.015). In contrast, `P-level' and body-size were significantly positively correlated (r = 0.40, P = 0.005). Body-size was also significantly positively correlated with mean-luteal-P (r = 0.45, P = 0.002) and mean-peak-P (r = 0.35, P = 0.015). Other than the correlation with body-size, there were no significant correlations between `P-level' and any single anthropometric variable nor with BMI (r = 0.02, P = 0.46) or body-fatness (r = 0.063, P = 0.35).
Figure 2 plots `P-level' against body-size, distinguishing Bol-p from Bol-b. It is evident that the observed correlation was not a spurious result of the shorter Bol-p women clustering apart from the taller Bol-b women. Correlation analyses for each of the samples revealed the same relationship, albeit with less statistical significance because of the smaller sample sizes.
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Discussion |
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The Bolivian participants selected for this study were carefully screened and, among Bol-b, progesterone indices and anthropometrics did not differ between nulliparous and parous women (i.e. those of `unproven fertility' did not have progesterone levels lower than those of `proven' fertility). Nearly all the Bol-p women are of `proven fertility' despite the lower progesterone levels characterizing their ovulatory cycles. Hence, the observed progesterone levels are very unlikely to be the result of a sampling bias towards women of lower fecundity.
The progesterone indices and method of ascribing ovulation proposed here avoid some of the methodological limitations of previous approaches. The factors derived from PCA better represent variation in progesterone levels and body-size and composition than any one index or single anthropometric variable. For example, in ovulatory cycles, individual progesterone indices are not significantly different between the Bolivian samples, but `P-level' (the factor capturing the totality of the progesterone profile) is significantly different.
Although tempting, comparisons of progesterone levels in these Bolivia samples with those observed in previous studies (Table I) are spurious because those participants had not met comparable exclusion criteria and the samples contained unknown numbers of ovulatory cycles, making it impossible to ascertain the significance of differences and similarities in progesterone levels.
The results of this study are consistent with hypotheses that current variation in progesterone, and fecundity in general, reflects both current (acute) and longstanding (chronic) variations in energy intake and expenditure as well as other potential determinants of reproductive success (Ellison, 1990, 1996
; Vitzthum, 1990
, 1997
, 2001
; Vitzthum et al., 2000
). It is a fundamental ecological principle that in adults of reproductive age, energy must be allocated to maintenance/repair or reproduction. Lifetime reproductive success in a given set of conditions may be increased if energy is efficiently allocated such that waste is minimized. Thus it may prove advantageous, over a lifetime, to temporarily suspend investment in reproduction if current conditions are such that a conception has a relatively poorer probability of resulting in a live birth and the survival of the child.
The Bol-p women had a higher parity than Bol-b women, although reported ages at menarche and first birth were comparable. Given this indisputable evidence of normal ovarian function over the long-term in the poorer Bolivian women, the observed high rate of anovulation is reasonably attributable principally to stressors acting at the time of the study. Specifically, these data were collected during the Bolivian winter months, a period when some of the very poorest urban dwellers can experience a temporary loss of food supplies from relatives on farms. Rather than pathological, the reduction in fecundity evidenced by the high rate of anovulation is appropriately viewed as an adaptive response to these short-term (acute) relatively limited resources.
Adaptation to long-term (chronic) conditions, on the other hand, may explain the lower progesterone levels, compared with Chicago, observed in ovulatory cycles of both Bolivian samples, and the relatively lower `P-level' of Bol-p compared with Bol-b. While not definitive, it may be assumed that the majority of these women were raised in conditions roughly similar to those of their adult economic status. Ample evidence (Bogin, 1999) argues that chronic nutritional deprivation during childhood and/or adolescence influences immune responsiveness and reproductive functioning, and results in relatively shorter adult stature. Significant anthropometric differences between Bol-b and Bol-p in height, body-size, and arm musculature all lend support to the presumption that Bol-p experienced relatively greater nutritional deprivation and perhaps greater physical labour during childhood. Given that variations in body-size seen both within and between the samples of Bolivian women are probably the result of differences in ecological conditions during childhood, the significantly positive correlation found between body-size and `P-level' suggests that variation in `P-level' in ovulatory cycles of adult women may also reflect such differences in developmental conditions.
The apparent paradox that lower progesterone is not necessarily associated, over the long term, with a reduction of reproductive output is resolved if evaluated from an evolutionary perspective. Based on known attributes of mammalian physiology and functioning and principles of life history theory, the Flexible Response Model (FRM) (Vitzthum, 1990, 1997
, 2001
; Vitzthum et al., 2000
) posits that selection favours a flexible reproductive system that reflects developmental conditions and responds to current ecological circumstances. Rather than viewing elevated progesterone in Chicago women as a `normal' standard below which reproductive functioning can be inferred to be impaired, the FRM hypothesizes that `normal' progesterone levels are established during pre-adult development as a result of the specific ecological conditions at the time and setting. From the perspective of the organism, the best conditions experienced during development are `optimal', even if less than ideal, so long as they are minimally adequate to support basic functioning. Therefore, the reproductive system functions `normally' under those conditions. Individuals unable to function in this way would have relatively low reproductive output and `lose' in the evolutionary process of natural selection. Hence, the significant difference in ovulatory cycle `P-level' among the samples is consistent with the hypothesis of the FRM that developmental conditions contribute to variation in adult reproductive functioning.
These findings are also relevant to understanding the aetiology of certain cancers. Changes in reproductive patterns (e.g. earlier menarche, fewer births, and reduced breastfeeding) that increase menstrual cycle frequency have been linked to increased risks of breast, endometrial and ovarian cancer (Eaton et al., 1994). US women also have relatively higher levels of reproductive steroids that may exacerbate cancer risks. Explanations for these levels include dietary and activity patterns, but definitive tests of these hypotheses remain elusive. This study suggests that conditions experienced during childhood may be an important aetiological factor underlying elevated reproductive steroids.
For example, the secular trend of increasing height in the US population over the last century is well documented and principally attributed to improved diet and reductions in infectious disease (Bogin, 1999). These Bolivian data predict that an increase in height (and overall body-size) will be associated with an increase in adult reproductive steroids. This relationship can explain, in part, the observation that second generation migrants to the US from populations characterized by relatively low reproductive steroids and shorter stature are found to have both relatively increased stature and elevated reproductive steroids. Also consistent with our findings, epidemiological studies have observed a strong positive association between body-size, particularly height, and risk of breast cancer (Ziegler et al., 1996
; Friedenreich, 2001
), and women in the high Andes have among the lowest age-adjusted risk of breast cancer worldwide (Pan American Health Organization, 1999
).
Our findings of naturally lower endogenous progesterone levels in these Bolivian women are also relevant to expressed concerns about appropriate hormonal contraceptive dosages for women in developing countries (Fotherby et al., 1980; Bassol et al., 1984
; Bentley, 1996
; Vitzthum and Ringheim, 2000
). Hormonal contraceptives that have been designed for women in industrialized countries may be excessively high for those in non-industrialized populations, resulting in an intolerable level of side-effects that leads to discontinuation and, potentially, unplanned pregnancy. While it remains to be determined if lower progesterone results from lower ovarian production or more rapid clearance by the body, during a decade of fieldwork the first author has often heard Bolivian women and health workers express concern about negative experiences with hormonal contraceptives. Contrary to arguments that non-compliance is more a matter of education than biology, the findings of this study suggest that the reports of these women regarding negative sequelae of hormonal contraceptives may well have a physiological basis.
These data contribute to an emerging reconceptualization of the complexity and subtlety of ovarian function. The significant difference in mean-follicular-P in ovulatory cycles between Bol-p and Chicago, and significant loading of `P-level' on mean-follicular-P in the PCA, challenge the assumption that follicular progesterone levels are uniformly constant and low. It is also noteworthy that all of the women in this study with anovulatory cycles were regularly menstruating. In exercising North Americans, menstrual irregularity or amenorrhoea typically accompanies anovulation (Bullen et al., 1985; Chen and Brzyski, 1999
), but this is best interpreted as the extreme in a continuum of ovarian response (Prior, 1985
; Vitzthum and Smith, 1989
; Ellison 1990
; Vitzthum, 1990
). For example, moderate recreational exercise was found to be associated with suppressed progesterone profiles but not amenorrhea (Ellison and Lager, 1986
). Finally, the range of progesterone accompanying normal ovulation in Bolivian women is lower than in Chicago women. Standard clinical practice considers progesterone levels <40% of `normal' to be anovulatory (Wilson et al., 1998
). In the Chicago sample, 40% of mean-peak-P is 132 pmol/l, 20% higher than the threshold of 110 pmol/l mean-peak-P determined in this study. Overall, normal variation in ovarian function is much greater than previously recognized.
A final note of caution is warranted when inferring support from these data for various models regarding cancer aetiology or the evolution of the human reproductive system. The sample sizes are not large, little is known of the developmental circumstances of the participants, nothing is known of the previous trajectory of progesterone levels, and the relative lifetime reproductive output of both poor and better-off samples remains to be realized. The findings, however, do indicate intriguing directions of research worthy of pursuit.
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Acknowledgements |
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Notes |
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References |
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Submitted on December 12, 2001; accepted on March 4, 2002.