Sunday, June 04, 2006

Give Us This Day

Give Us This Day our daily germs

Graham A.W. Rook and John L. Stanford

Modern vaccinations, fear of germs and obsession with hygiene are depriving the immune system of the information input upon which it is dependent. This fails to
maintain the correct cytokine balance and fine-tune T-cell regulation, and may lead to increased incidences of allergies and autoimmune diseases. If humans continue to deprive their immune systems of the input to which evolution has adapted it, it may be
necessary to devise ways of replacing it artificially.

Ovarian aging: Is there a "norm"?

Ovarian aging: Is there a "norm"? Norbert Gleicher, MD

Female fertility declines with advancing age, principally because of changes in ovarian function. Ovarian aging always has been assumed to be the main culprit, but experience with human egg donation confirms that female fertility can basically be prolonged almost indefinitely, as long as "young" eggs are used in assisted reproduction.1

The decline in human fertility is predictable and can be quantified. Indeed, various authors have demonstrated that the downturn in women's fertility is the consequence of an age-dependent reduction in the number of remaining follicles, which starts during embryogenesis and continues. The initial pool of primordial follicles—at 16 to 20 weeks of fetal life—is believed to encompass approximately 6 to 7 million oocytes. At birth, the female's ovaries contain only 2 million oocytes, and by menarche, about 300,000 remain.2 That number is more than sufficient, as only about 450 monofollicular ovulations are required during a reproductive life of approximately 30 years.

Yet the number of remaining follicles does appear to matter, because when the follicular count falls to about 25,000—as it does in a physiologically normal ovary at approximately age 37.5—the decline in follicular numbers accelerates.3 Various authors, therefore, have suggested that what determines when a woman will experience menopause is not her age but how quickly her follicular count drops to approximately 1,000, the quantity at which menopause usually occurs.4 On average, that happens at age 51, or about 13 years after a woman reaches the 25,000-follicle milestone. In other words, at about age 37.5, a woman's fertility begins to accelerate, and about 13 years later, menopause sets in.

Age-Related Analysis of Inhibin A, Inhibin B

Relative to the Intercycle Monotropic Follicle-Stimulating Hormone Rise in Normal Ovulatory Women
Nancy A. Klein, Brenda S. Houmard, Karl R. Hansen, Teresa K. Woodruff, Patrick M. Sluss, William J. Bremner and Michael R. Soules

Previous studies have reported that the monotropic rise in FSH in older women is associated with decreased inhibin B and/or A levels and increased levels of activin A. Whereas most investigators have found decreased follicular-phase inhibin B, the roles of inhibin A and activin A as modulators of the FSH rise are unclear. The objectives of this study were to determine whether deficiencies in circulating levels of inhibin A, inhibin B, and/or activin A exist during the intercycle interval in ovulatory older (age, 40–45 yr; n = 16), compared with younger women (age, 20–25 yr; n = 13). Blood samples were obtained daily throughout one menstrual cycle and the follicular phase of the subsequent cycle and were analyzed for LH, FSH, estradiol, inhibin A and B, and activin A. Despite significant FSH elevation, no deficiencies in inhibin A, activin A, or estradiol were detected in older subjects. In fact, inhibin A was significantly higher in older participants during the intercycle phase (P = 0.01), whereas inhibin B was significantly lower. Thus, the monotropic rise in FSH does not appear to result from changes in inhibin A or activin A, supporting the concept that inhibin B plays a critical role in mediating the FSH rise in older women.

The 13 Year Window

The premise brought forth (Nicolaou and Templeton, 2003Go) is that there is a 13-year window between the beginning of the accelerated phase of atresia (38 years) and the average age of menopause (51 years).

Nikolaou, D. and Templeton, A. (2003) Early ovarian ageing: a hypothesis. Detection and clinical relevance. Hum. Reprod., 18, 1137–1139

There are two general concerns challenging this hypothesis.....

The second issue is the ‘fixed’ nature of this window of 13 years. Basically, we just do not know if this is the case. While it was originally assumed that oocyte loss occurred as a constant logarithmic function (Block, 1952Go), it is more accepted now that there is an accelerated depletion after age 38 years (Richardson et al., 1987Go; Gougeon et al., 1994Go).

Block, E. (1952) Quantitative morphological investigation of the follicular system in women. Acta Anat., 14, 108–123

Richardson, S.J., Senikas, V. and Nelson, J.F. (1987) Follicular depletion during the menopausal transition. Evidence for accelerated loss and ultimate exhaustion. J. Clin. Endocrinol. Metab., 65, 1231–1237

Gougeon, A., Ecochard, R. and Thalabard, J.C. (1994) Age-related changes of the population of human ovarian follicles: Increase in the disappearance rate of non-growing and early-growing follicles in aging women. Biol. Reprod., 50, 653–663.

However, it is not at all clear what the variability is in the slope of this line. Rate of atresia may be variable in different women, and this variability may occur before age 38, as well as in the time period after age 38. At least two conditions have been theorized to alter (increase) the rate of atresia (genetic variations in the X chromosome and thymectomy) (Singh and Carr, 1966Go; Lintern-Moore, 1977Go)

The 13-year window (which is assumed to be the average time frame for women) may not be 13 years per se and is likely to be less or more on an individual basis.

The Impact of age on Female Fertility

Over the past several decades, demographic and socioeconomic trends have resulted in an increase in the absolute number of women seeking pregnancy in their late 30’s and early to mid-40’s. In addition, a significant number of women in this age group are seeking evaluation and treatment for infertility. Although there is a very well demonstrated decline in female fertility as a function of age, this phenomenon has typically has been under-recognized not only by the general population, but also by many health care providers. This is probably related to the fact that in previous decades women generally had completed childbearing by the late 30’s and in fact many of the pregnancies that occurred in the later reproductive years were unplanned. An increased awareness of the effects of aging on fertility for patients and health care providers is critical to the prevention of age-related infertility.

continue reading

Age and Infertility. The Biological Clock, fact or fiction?

With recent dramatic advances in infertility treatment, age related infertility remains as one of our most difficult challenges. Reproductive specialists have known for years that the pregnancy rate is inversely related to the female partner's age. Early explanations for this trend included decreased coital frequency, diminished desire for childbearing, decreased overall time to try for a pregnancy, and diminished ovarian reserve with advancing age.1,2 Today, we would add increased spontaneous abortion, oocyte depletion, and oocyte aging to the list.3 Coupling this issue of age with our current societal trend of increased numbers of women who delay childbearing for educational and career goals, we now have a dramatic increase in age related infertility. For those providing primary care to women, it is now much more important to carefully counsel patients regarding family planning issues, especially with regards to advancing age and diminished pregnancy rates. Patients who are in their early to mid thirties or beyond who are considering pregnancy or have been trying for any length of time without success warrant an early referral for evaluation.

Here's Another One

"As expected, advancing female age was strongly associated with reduced fertility. The day-specific probabilities of pregnancy were observed to decline in women in their late 20s, slightly earlier than reported in the CECOS study of women with artificial insemination (Fédération CECOS, 1982). Nearly a 50% drop occurred between women in their early 20s and women in their late 30s. These estimates do not include the increased occurrence of spontaneous abortion that is evident in older women, but do include early, preclinical loss, which is not distinguishable from non-conception in these data."

Changes with age in the level and duration of fertility in the menstrual cycle
David B. Dunson1, Bernardo Colombo and Donna D. Baird

Here the CECOS study:

Female fecundity as a function of age: results of artificial insemination in 2193 nulliparous women with azoospermic husbands. Federation CECOS.

Schwartz D, Mayaux MJ.

PIP: Fecundity has been reported to decline in women over 30 years of age. It is not known whether the decrease in fecundity is biologic or simply the consequence of diminished sexual activity. Artificial insemination with donor semen (AID) offers an opportunity to control certain variables in the study of female fecundity over time. 2193 nulliparous women who were receiving AID from 1973-80 at the Centres d'Etude et de Conservation du Sperme Humain (CECOS) and whose husbands were totally sterile were studied. The women were divided into 4 age groups: 25 years old or younger (n=371), 26-30 (n=1079), 31-35 (n=599), and 35 or older (n=144). At the end of the study period, the women were categorized into 4 groups, depending on the outcome: success (all pregnancies occurring during the study period), lost to follow-up (if the result of the last AID cycle was unknown), open case (result of last AID cycle was known but the next insemination procedure had not yet taken place), and dropout (discontinued treatment). The cumulative success rates were calculated ater 12 cycles with the life table technique adapted to AID as if there were no dropouts (theoretical cumulative rates). The Mantel-Haenzel test was used to compare the curves obtained from the cumulative rate as a function of the number of treatment cycles for the various age groups. The 4 curves differed significantly (chi-square=15.72, with 3 degrees of freedom; p0.01). The curves for the 2 age groups under 30 were very similar. Overall, the study shows that a decrease in fecundability (conception rate per cycle) as a function of a woman's age is slight but significant after 30 years of age and marked after 35 years. The probability of success of AID for 12 cycles declined to 61% (from 73% for those under 31 years old) for the 31-35 age group (p0.03) and to 54% (from 74% for those under 31 years old) for those over 35 (p0.001). 2 major problems encountered in studying variations in fecundity as a function of a woman's age are: 1) the need to separate the effect of the woman's age from associated variables such as coital pattern and husband's age, and 2) the woman's age itself, which could result in bias, since time introduces a type of selection. AID may provide the best means of minimizing the effects of associated variables and sources of bias.

Here It Is!

Follicle dynamics during ovarian ageing.
Faddy MJ
Mol Cell Endocrinol. 2000 May 25;163(1-2):43-8.

The human ovary is endowed at birth with a fixed number of primordial follicles which steadily declines throughout life as a result of atresia and recruitment towards ovulation. The pattern of this decline is not exponential, but more bi-exponential corresponding to a 'broken-stick' regression of logged total numbers of follicles against age. Such a model implies an abrupt change in the exponential rate of follicle loss at age 38 years, and is thus rather implausible biologically. A more refined model with an exponential rate of follicle loss that changes gradually throughout life also describes the data on declining follicle numbers but in addition leads to a distribution of age at menopause, corresponding to follicle numbers falling below a critical threshold, that shows quite remarkable agreement with independent data on menopausal ages of American women. When the follicles are classified into resting and growing stages, it is found that any changes in the consequent process of follicle development as the ovary ages relate mainly to the small resting follicles and not the larger growing ones.

Power point presentation:

Premature Ovarian Aging and Infertility

Fetal Growth Retardation and Ovarian Development

Fetal growth retardation as a cause of impaired ovarian development

J. P. de Bruina, M. Dorlanda, H. W. Bruinsea, W. Splietb, P. G. J. Nikkelsb and E. R. Te Veldea


Low birthweight has been associated with diseases and disorders later in life. It has been suggested that this is caused by the impaired development of abdominal organs, especially in cases of growth retardation. Besides general malnutrition of the fetus, preferential bloodflow to the heart and brain may further deprive organs, such as liver, pancreas and kidney, of nutrients. As a result these organs may not develop properly. Anatomically, the ovary is situated close to the kidney and it is very likely that, similar to the kidney, ovarian development can be negatively affected by intra-uterine growth retardation. Placental insufficiency, which is an important cause of severe intra-uterine growth retardation, was used as a model to investigate this hypothesis. In the present study, the volume percentages of primordial follicles in the ovaries of four severely growth-retarded fetuses of different gestational ages are compared to those of four age-matched controls. It is found that these volume percentages in growth-retarded fetuses were significantly lower than those observed in the age-matched controls. It can be concluded that ovarian development is impaired in intra-uterine growth-retarded fetuses. These findings further suggest that, as a result of the premature loss of follicles, females with low birthweights may encounter fertility problems later in life.

Morphometry of human ovaries in normal and growth-restricted fetuses

J. P. de BruinCorresponding Author Contact Information, E-mail The Corresponding Author, a, P. G. J. Nikkelsb, H. W. Bruinsec, M. van Haaftena, C. W. N. Loomand and E. R. te Veldec


According to the fetal origins hypothesis, normal growth and development of abdominal organs is disturbed by intra-uterine growth restriction, leading to diseases later in life. The aims of this study were to investigate the effect of growth restriction on the ovaries of human fetuses and to investigate the dynamics of follicular growth in normal fetuses. We selected 21 normal female fetuses (controls) and seven severely intra-uterine growth-restricted female fetuses (IUGR cases) from all autopsy records over a 10-year period. Ovarian volume was calculated and from histological sections the volume-percentage of follicles in the ovarian cortex, the maximum diameters of individual follicles and the distribution of the follicle classes and oogonia were determined. The volume of the ovaries increased significantly from 0.10 to 0.36 cm3 in the second half of gestation. The mean volume-percentage of ovarian follicles and the mean follicle diameter significantly increased with 0.48% and 0.52 μm per week, respectively. Class B/C (intermediary) follicles (72%) were predominantly present. Class B (primordial) follicles decreased from over 20% to less than 10% and class C (primary) increased from 6 to 19%. Class A (oogonia) were frequently present before 30 gestational weeks, but were rare after that age. For all studied parameters we did not find differences between IUGR cases and controls. Intra-uterine growth restriction does not seem to disturb ovarian development in the human fetus. In the second half of gestation the follicle pool increases by the growth of individual follicles, the transition of follicle to larger classes, and probably by increasing follicle numbers. As most follicles at term were class B/C and C, follicles up to class C are probably part of the resting stock.

Aspects of Ovarian Follicle Development throughout Life
, N.S. Macklon, B.C.J.M. Fauser


The pool of primordial follicles present in the female ovary reaches its maximum number around 20 weeks of gestational age and then decreases in a logarithmic fashion throughout life until complete depletion occurs around the age of the menopause. Reproductive life is initiated when less than 10% (0.5 million) of primordial follicles are left. The entire growth trajectory of the follicle takes at least 3 months. Follicle growth up to the antral stage occurs during fetal life and infancy. While the role of gonadotropins in early follicular development remains controversial, the last 2 weeks of development are FSH dependent. The intercycle rise in FSH and decreasing levels thereafter are crucial for recruitment of a cohort of healthy, early antral follicles and subsequent single dominant selection. Following puberty, anovulation may persist for years and this may presage the development of adult anovulatory infertility. The menopause is preceded by a period of reduced fertility. The development of reliable and sensitive markers for ovarian ageing will be the challenge of the near future.

Lourdes Ibañez, Menarche and Low Birth Weight

I am currently looking at lower age at menarche, speed of transition to the lower ages, and fertility impacts. The big conjecture would be that there should be a negative impact of this process on final achieved TFRs in the context of a systematic and continuing birth postponment process. To date I have nothing conclusive on this one way or the other.

However I have identified two secondary feedback mechanisms which do seem to influence long term fertility:

a) A correlation between obesity and lowest low menarche. Now obestity is also a fertility inhibiting correlate.

b) A relationship between reduced birth weight, lower age at menarche (due to subsequent cath-up growth) and reduced lifelong fertility.

Here the work of Lourdes Ibañez seem to be very important:

Early Puberty-Menarche After Precocious Pubarche: Relation to Prenatal Growth
Lourdes Ibáñez, MD, PhDa, Rafael Jiménez, MD, PhDa and Francis de Zegher, MD, PhDb

RESULTS. At the time of PP diagnosis, age, bone age, and BMI were similar across birth weight subgroups; circulating sex hormone–binding globulin and body height were reduced in PP girls with lower birth weight, and these remained so throughout pubertal development. Onset of puberty occurred earlier in PP girls with lower birth weight; so did menarche. Adult height differed by an average of 6.5 cm (~1 SD) between the upper and lower birth weight subgroups; this difference was essentially achieved before puberty and even before PP. Menarche before age 12.0 years was twofold more prevalent in PP girls than in control subjects. Among PP girls, age at menarche was advanced by 8 to 10 months in lower versus higher birth weight girls. Menarche before age 12.0 years was threefold more prevalent among LBW-PP girls than in control subjects (~75% vs ~25%).

CONCLUSIONS. The link between prenatal growth restraint and early menarche is herewith extended to PP girls. In particular LBW-PP girls may become a target group for interventions directed toward normalization of pubertal onset and progression.

Reduced Ovulation Rate in Adolescent Girls Born Small for Gestational Age

Lourdes Ibáñez, Neus Potau, Angela Ferrer, Francisco Rodriguez-Hierro, Maria Victoria Marcos and Francis de Zegher

Interestingly for the bigger issue Lourdes here finds a more rapid ovulation rate in post menarche children than previously reported:

"This is a first study assessing adolescent ovulation rate over 3 months, on an ambulatory basis, through weekly measurements of progesterone concentrations in capillary blood dried on filter paper. With this novel method, 23 of 24 participating AGA (appropriate for gestational age) girls were found to have at least one ovulatory cycle within 3 months. This ovulation rate (96%) is, so far, the highest reported in adolescents (16, 17), suggesting that this technique has a sensitivity superior to previous methods (17). Moreover, it is unlikely that this simple method overestimates ovulation rate because the time lag between the proposed ovulation date and the onset of the following menses was uniformly consistent with the time course of a normal ovulatory cycle."


"The ovulation rate in SGA (small for gestational age) girls was found to be strikingly low; the anovulatory fraction was much larger than in the AGA girls. Moreover, in ovulatory SGA girls, the individual number of ovulations over 3 months was also reduced. Interestingly, the reduction in ovulation rate was comparable in SGA adolescents who had reached a stature within target range and in SGA girls with a postmenarcheal stature that was below target level. This observation suggests that anovulation secondary to prenatal growth restraint is a phenomenon that is essentially unrelated to completeness of spontaneous catch-up growth. Thus, in SGA girls, spontaneous recovery of linear growth during childhood does not warrant normal ovulatory function in adolescence; conversely, persistent growth failure in SGA girls will not necessarily be followed by anovulation."

"That the link between reduced prenatal growth and anovulation has apparently escaped attention for so long may in part be attributable to the fact that the majority of SGA girls normalize their stature, and hereby no longer present an obvious reminder of their early growth restraint. The copresence of obesity may have been another notoriously confounding factor in ovulation research; the absence of obesity in the described study population has presumably facilitated the disclosure of the link between prenatal growth and postmenarcheal ovulation rate."

"Prenatal growth restraint has previously been documented to be associated with relative hyperinsulinism, hyperandrogenism, and FSH hypersecretion in adolescent girls from Catalunya (5, 18, 19). These associations were confirmed in the present cohort and may each contribute to the reduced ovulation rate in SGA adolescents."

Ibáñez L, Potau N, de Zegher F 2000 Ovarian hyporesponsiveness to follicle stimulating hormone in adolescent girls born small for gestational age. J Clin Endocrinol Metab 85:2624–2626

Ibáñez L, Potau N, Marcos MV, de Zegher F 1999 Exaggerated adrenarche and hyperinsulinism in adolescent girls born small for gestational age. J Clin Endocrinol Metab 84:4739–4741

Ibáñez L, Valls C, Miró E, Marcos MV, de Zegher F Early menarche and subclinical ovarian hyperandrogenism in girls with reduced adult height after low birthweight. J Pediatr Endocrinol Metab 15:431–433

Ibáñez L, Valls C, Ferrer A, Ong K, Dunger D, de Zegher F 2002 Additive effects of insulin-sensitizing and anti-androgen treatment in young, non-obese women with hyperinsulinism, hyperandrogenism, dyslipidemia and anovulation. J Clin Endocrinol Metab 87:2870–2874

"In conclusion, the endocrine correlates of prenatal growth restraint are herewith extended to include oligo-ovulation and anovulation in adolescence. It remains to be verified whether this SGA-related phenomenon persists into the reproductive age range. If it does, then fetal growth restraint may prove to be one of the enigmatic components underpinning hitherto unexplained female subfertility."

Here's a page summarising Lourdes's work (in Catalan).

Saturday, June 03, 2006

China Menarche II

"Southern Chinese girls aged 11 years and 9 months to 12 years and 3
months in Hong Kong have a mean menarcheal age of 11.50 years
(standard deviation of 0.47) using the recollection method. Highly
significant differences are found when compared to the 12-year-old
girls in Hong Kong studied in the past decades. Therefore, a secular
trend of earlier menarcheal age is demonstrated.

So, LL, Yen, PK. Secular trend of menarcheal age in southern Chinese girls.
Z Morphol Anthropol. 1992 Jun;79(1):21-4.

Huen, KF, Leung, SS, Lau, JT, Cheung, AY, Leung, NK, Chiu, MC. Secular
trend in the sexual maturation of southern Chinese girls. Acta
Paediatr. 1997 Oct;86(10):1121-4.

"In 1993, a cross-sectional study of sexual maturation of normal
Chinese schoolgirls was performed in Hong Kong. The aim of the study
was to obtain an up-to-date reference for normal pubertal development
in Chinese girls. ... Menstrual status was recorded in 6467 girls over
6 y of age. ... The median age of menarche was 12.38 (95% CI
11.98-12.78) years. ... When comparison is made with similar studies
done in 1962 and 1979, a significant downward secular trend in sexual
maturation is observed (p < 0.01). Except for breast development the
downward secular trend in sexual maturation appears to be diminishing
and may be coming to a halt in the Chinese girls in Hong Kong. Their
median ages of sexual maturation are now among one of the earliest
medians recorded in the world population studied."

Growth status and menarche in urban and rural China
T. Hesketh, Qu Jian Ding, A. Tomkins


Objective: To examine the relationship between current age at menarche and growth status in an urban and rural area of Eastern China. Study design: Cross-sectional survey: self-completion questionnaire and anthropometry in 12 schools in urban Hangzhou and rural Chunan in Zhejiang Province. Results: The median menarcheal age calculated by probit analysis was significantly different in the two areas: 12.8 years (SD 0.9) in the urban area and 13.2 (SD 1.0) in the rural area (p < 0.001). Girls who reach menarche are significantly heavier and taller with higher BMIs than those of the same age who are pre-menarche. After adjustment for BMI and other possible confounders, urban girls were still menstruating significantly earlier than girls in rural areas (OR 3.3, 2.1-5.2). Conclusions: The age of menarche is probably still declining in China. Although BMI is an important factor in the onset of menstruation, some other unmeasured environmental variable may be implicated in this population.

Germany Menarche

Changes in age at menarche in Germany: Evidence for a continuing decline
Dörte Ostersehlt, Heidi Danker-Hopfe


Since there are no recent data on secular changes in growth and maturation of girls from West Germany, two cross-sectional studies with equal design have been carried out in Bremerhaven, North Germany, in 1979/80 and 1989. The present paper presents the results of an analysis of changes in age at menarche based on status quo data from school girls (1979/80: 2,796; 1989: 2,223) aged between 10.0 and 18.5 years. Probit analyses show a reduction over the 10-year period from 13.30 ± 1.19 to 13.01 ± 1.21 years, while logit analyses, which fit the empirical data slightly better, show a reduction from 13.29 ± 1.21 to 13.00 ± 1.24 years.

Croatia Menarche II

Secular growth changes in Zagreb schoolchildren over four decades, 1951–91

Ž. Preberg, V. Jureša, M. Kujundžić


Secular changes in growth and development vary over past decades in intensity and in trend. The purpose of this paper is to present changes in growth patterns of Zagreb schoolchildren aged 7–19 years over the past four decades. Surveys were performed in 1951, 1964, 1973, 1982 and 1991. The mean height of boys and girls in all observed groups has increased significantly over the 40-year period. Age groups up to 9 years in 1991 were 4–7·5 cm taller than their coevals in 1951. Differences increased from the age of 10 in girls and 12 in boys, reaching 10 cm in girls of 12 years and even 14 cm in boys of 14 years. They were also highly pronounced in adult height (5 cm in girls, 7 cm in boys). The most pronounced changes appeared from 1951 to 1964, while in the period from 1964 to 1973 the increase was smaller; in girls only up to 13 years, in to 17 years. However, between 1973 and 1982 positive changes were again significantly pronounced, especially in the older age groups. In the last period, 1982–91, the trend seemed to come to an end. Changes in average weight mostly corresponded to the height changes, being somewhat greater in boys. Moreover, in the last two periods, weight gain in older girls was smaller compared to height. Menarche in the period 1964–73 shifted to a younger age by 8 months (13·34–12·67 years), retaining the same level over the next 9 years. However, since 1982 a slight reverse trend has been noticed.

Denmark menarche

A continuous decline in menarcheal age in Denmark
Annette W. Olesen, Bernard Jeune, Jesper L. Boldsen


We report a renewed decline in mean menarcheal age in a large Danish sample after a period with a halt in the trend towards earlier age at menarche in many North European countries. In our study based on retrospective data from six different samples constituting 42784 women, we find a continuously declining mean menarcheal age in Denmark among women born in the years 1964-1973. In a sample of textile workers born in the years 1939-1968 (n = 12605) we find a 1 year higher mean menarcheal age. This indicates that menarcheal age is still delayed in certain groups in Denmark. This leaves the possibility that the menarcheal age could fall even further in the future.

Croatia Menarche

Changes in menarcheal age in girls exposed to war conditions
ivka Prebeg, Irena Brali


The purpose of this study was to assess changes in mean menarcheal age of girls in the city of ibenik in the period from mid-1980s to the mid-1990s. ibenik is a Dalmatian town which was exposed to hard war conditions in 1991-1995. Menarcheal status of ibenik girls was surveyed three times, in 1981, 1985, and 1996, and included 720, 1,207, and 1,680 girls, respectively, ages 9.5-16.5 years. Mean menarcheal age was estimated by the status quo method and application of probit analysis. Results show a slight decrease in menarcheal age from 1981 to 1985 (from 12.97 ± 0.06 years to 12.87 ± 0.05), and then a significant increase from 12.87 ± 0.05 years in 1985 to 13.13 ± 0.10 years in 1996. The increase in mean menarcheal age occurred in all socioeconomic groups based on parental occupation and number of siblings. In the group of girls whose homes were damaged during war, menarche occurred at an average of 13.53 ± 0.14 years, while those who lost a family member experienced menarche at an older mean age, 13.76 ± 0.27 years. However, when the girls who experienced personal tragedies were excluded the onset of menarche was still later than in girls surveyed in the earlier periods. The results suggest that the general reversal in the secular trend of menarcheal age in ibenik girls can be attributed to persistent psychological pressures and uncertainties associated with conditions of war. Am. J. Hum. Biol. 12:503-508, 2000.

Belgium Menarche II

"The age at menarche in a national sample of 4894 Flemish schoolgirls
was surveyed in 1979-1980. The probit estimate of the mean age at
menarche was 13.20 +/- 0.02 years (SD = 1.25 years). ... Status quo
secular data for the 20th century indicate a decline in estimated mean
ages at menarche of Flemish girls from about 14.3 years before World
War II to 13.6 and 13.2 years, respectively, among girls born just
before and during the war. Subsequently, mean ages at menarche of
Flemish girls are fairly stable between 13.0 and 13.2 years. These
secular changes are of the same magnitude as those observed in other
European countries."

Wellens, R, Malina, RM, Beunen G, Lefevre J. Age at menarche in
Flemish girls: current status and secular change in the 20th century.
Ann Hum Biol. 1990 Mar-Apr;17(2):145-52.

Netherlands Menarche

"Since 1858, an increase of mean stature has been observed in the
Netherlands, reflecting the improving nutritional, hygienic, and
health status of the population. In this study, stature, weight, and
pubertal development of Dutch youth, derived from four consecutive
nationwide cross-sectional growth studies during the past 42 y, are
compared to assess the size and rate of the secular growth change. ...

In girls, median age at menarche has decreased by 6 mo during the
past four decades to 13.15 y.

Fredriks AM, van Buuren S, Burgmeijer RJ, Meulmeester JF, Beuker RJ,
Brugman E, Roede MJ, Verloove-Vanhorick SP, Wit JM. Continuing
positive secular growth change in The Netherlands
1955-1997. Pediatr
Res. 2000 Mar;47(3):316-23.

Pubertal Development in The Netherlands 1965–1997

We conclude that the secular change toward earlier puberty has been stabilized in the last two decades in The Netherlands. No change in the definition of precocious puberty is warranted. The occurrence of menarche is not only dependent on age, but
also on height, weight, and BMI. Beyond a weight or BMI of .0 SDS, this dependency is less apparent. The agreement between the expression of gonadal maturation and pubic hair is slightly higher in boys than in girls.

Menarche Spain

Secular change in menarche in women in Madrid
C. Prado
Annals of Human Biology, Volume 11, Number 2 / March / April 1984


The age at menarche was estimated by recollection in 1617 women between the ages of 18 and 60 in Madrid and a nearby suburb, Pinto. The population of Pinto is working-class and the Madrid group, taken from residential neighbourhoods, belongs to the upper middle class. In both groups we found a diminution in average age at menarche, from 14·04 to 13·02 years in Madrid and from 14·55 to 13·16 years from about 1935 to about 1965 in Pinto. These changes have been more intense in the group which is less well-off economically, where living conditions have varied much more drastically.

Cambio secular en crecimiento y ciclo reproductor femenino
en la población madrileña en las últimas seis décadas

El cambio secular respecto a las variables de ciclo reproductor ha sido detectado en varios estudios (Bernís, 1980; Prado, 1982; Danke-Hopfe, 1986; Eveleth y Tanner, 1990), conlleva un remarcable descenso en la edad de menarquia, tanto en ambientes rurales como urbanos, una menopausia cada vez más tardía y una mayor duración de los periodos reproductivos útiles, como consecuencia de la modificación de las dos variables anteriores.

El presente estudios, confirma un adelantamiento de la edad de menarquia, siendo la
diferencia total de 13 meses, y muestra una tendencia hacia una maduración más temprana observada anteriormente en España por Bernis (1980) y Prado (1982), entre otros autores. Al ser un carácter muy sensible a los cambios ambientales, la edad de menarquia supone un buen indicador de las condiciones socioambientales en las que han madurado las mujeres del estudio. La disminución en la edad de menarquia se observa en los grupos de menor edad, debido a las mejoras en las condiciones de vida; además se percibe un aumento en la edad de la primera menstruación en las mujeres de edades entre 60 y 69 años, mujeres que nacieron entre 1934 y 1943 lo que implica que pasaron su infancia y juventud en los años de posguerra ya que la guerra civil española transcurre entre los años 1936-1939. Esto explica también la edad de menarquia encontrada en el grupo de mayor edad (mujeres nacidas antes de 1934). Debido a que es un parámetro muy ecosensible (Bernis, 1980; Prado, 1982, 1984b) se ve afectado también por las condiciones desfavorables.

Algunos estudios detectan la persistencia de una tendencia secular respecto a esta variable en países como Turquía (Ersoy et al., 2004), Portugal (Padez y Rocha, 2003), Italia (Bona et al., 2002), etc., que estaría teniendo lugar a nivel mundial, aunque en algunos países, como en Hungría, parece evidenciarse una tendencia hacia la estabilización (Bodzsár y Zsakai, 2002).

Ersoy, B., Balkan, C., Gunay, T., Onag, A., Egemen, A., 2004, Effects of different socioeconomic conditions on menarche in Turkish female students. Early Human Development, 76, 115-125.

Padez, C., Rocha, M.A., 2003, Age at menarche in Coimbra (Portugal) school girls: a note on the secular changes. Annals of Human Biology, 5, 662-632.

Bodzsár, É.B., Zsakai, A., 2002, Some aspects of secular changes in Hungary over the twentieth century. Collegium Antropologicum, 26, 477-484.

A Life Course Study about Menarche

A Life Course Study about Menarche, Made Feasible by the Health and Demographic Surveillance System in Matlab, Bangladesh


This study is about the age at menarche (a biomarker) of adolescent girls in Matlab, Bangladesh, and the relative impact of contemporary and early childhood nutritional determinants. Application of the life course perspective requires analyses of longitudinal data. The study involves the follow-up of 707 under-five children who were enrolled in a study on persistent diarrhoea conducted in Matlab in 1988-1989 by Baqui. The follow-up survey took place in 2001. By that year the under-fives had grown up to adolescents, aged 12 to 16 years. Tracing the adolescents was feasible because of the Health and Demographic Surveillance System, which is maintained in Matlab. The results reveal that the relative high median age at menarche (15.1 years) is associated with stunting in early childhood and particularly in adolescence. The study is an example of the further integration of the life course approach to reproductive health research within the discipline of demography.

Effect Of Womens’ Nutrition Transition On Infant Survival In India

Food habits are the ways in which individuals or groups of persons respond to social and cultural pressures, choose and consume and make use of available foods (Mcad, 1962).As populations becomes more westernized, dietary compositions changes to include more saturated fats and less fibre. Although this leads to dense diets, the actual energy intake may not be greater which increases womens’ susceptibility to anaemia and becoming underweight and lead to abortion and still birth etc.

continue reading

International Comparisons of Menarche

Here's the Frederic Thomas comparison study.

Menarche Haiti

"Trends in age at menarche of 10,563 pregnant Haitian women enrolled
in a longitudinal study of maternal mortality are examined. Mean
recalled age at menarche for adult women in the sample was 15.37
years. However, there was a clear decline in mean menarcheal ages from
the oldest to the youngest women, with a mean rate of decline for
adult women of 0.36 years per decade. ...The data suggest a secular
decline in age at menarche in Haiti"

Barnes-Josiah D; Augustin A. Secular Trend in the Age at Menarche in


Trends in age at menarche of 10,563 pregnant Haitian women enrolled in a longitudinal study of maternal mortality are examined. Mean recalled age at menarche for adult women in the sample was 15.37 years. However, there was a clear decline in mean menarcheal ages from the oldest to the youngest women, with a mean rate of decline for adult women of 0.36 years per decade. Mean menarcheal age was higher in each age group of rural women than for women in the metropolitan Port-au-Prince area; the rate of decline for adult rural women (0.37 years per decade) was nonsignificantly higher than that for adult metropolitan women (0.30 years per decade). The data suggest a secular decline in age at menarche in Haiti, as well as a continuing disparity between metropolitan and rural women. A declining age at menarche has important implications for fertility and reproductive health in Haiti, and may reflect a gradual improvement in health and nutritional status.

Menarche Brazil

Secular trend in age at menarche for women born between 1920 and 1979 in Rio de Janeiro, Brazil
G. Kac, M. Auxiliadora De Santa Cruz Coelho, G. Velasquez-Melendez


Primary objective: This article presents data on the secular trend in age at menarche for 1955 women from 16 to 76 years of age born between 1920 and 1979 and studied under the Nutrition and Health Survey conducted in the municipality of Rio de Janeiro, Brazil, in 1996.

Methods and procedures: Age at menarche was defined by the retrospective method. Women were grouped according to decade of birth, and the trend was estimated using simple linear regression between age at menarche and year of birth for the following specific periods: 1920-1940, 1920-1960, 1960-1979 and 1920-1979.
Main outcomes and results: Mean age at menarche decreased from 13.07 to 12.40 years when comparing the group of women born in the 1920s with the 1970s birth cohort, corresponding to a mean rate of -0.0123 years per year (p < 0.001). The downward trend was -0.0120 years per year (p > 0.05) for the 1920s, 30s and 40s, -0.0093 years per year (p < 0.05) for the period from 1920 to 1960, and -0.0224 years per year (p < 0.01) for the 1960s/70s.

Conclusions: The results suggest a secular trend in age at menarche. The literature points to such environmental variables as improved living conditions and expanded access to health services. Within this context, age at menarche could be used as a marker for social development.

Menarche China

Analysis pertains to 5-year birth cohorts during 1949-78 compared to
all cohorts born before 1949. MAM [mean age at menarche] declined from
16.5 years to 13.7 years over a 40-year period. The trend was linear.
... Findings suggest a similar MAM for Anhui province as for China as
a whole."

Graham MJ, Larsen U, Xu X.Secular trend in age at menarche in China: a
case study of two rural counties in Anhui Province.J Biosoc Sci. 1999

There is increasing evidence that age at menarche has decreased in Europe and the United States during the last century and in Japan over the last several decades. Data from a community-based survey conducted in two rural counties of Anhui Province in China indicate a similar, downward secular trend in age at menarche for Chinese women. The present study shows the mean age at menarche decreased by 2.8 years, from 16.5 to 13.7, over an approximate 40-year time interval. This rapid decrease in age at menarche may partly be due to better nutrition and living standards reflected by the improved socioeconomic standards experienced in China over the past few decades. To test this hypothesis, a number of determinants of age at menarche were assessed; year of birth, literacy status, county of residence, amount of physical labour, general health status, pesticide exposure before age at menarche, and drinking water source were all found to be associated with age at menarche.

PIP: This study examined determinants of the mean age at menarche (MAM) in 2 rural counties (Zongyang and Huaining) of Anhui province, China. Data were obtained from a 1993 household community survey among about 12,727 Han women. Years of age were adjusted to account for the Chinese lunar calendar. Analysis pertains to 5-year birth cohorts during 1949-78 compared to all cohorts born before 1949. MAM declined from 16.5 years to 13.7 years over a 40-year period. The trend was linear. Year of birth and level of education were strongly related to a decrease in MAM. MAM was also significantly associated with county, physical labor, general health status, exposure to pesticides before age at menarche, and water source. Year of birth explained most of the difference in MAM. There were no significant interactions between birth year and literacy, water source, or pesticide exposure, or between county and amount of physical labor. Women from Zongyang county had a later MAM than women from Huaining. Illiterate women had a higher MAM than literate women. The decline in MAM is attributed to improved nutritional status and living standards since World War II. 788 women reported a MAM that was older than 19 years. Subtracting these women only resulted in a decrease in MAM to 15.9 years for the pre-1949 cohort. Findings suggest a similar MAM for Anhui province as for China as a whole.

Menarche Belgium

The secular trend of height and menarche in Belgium: are there any signs of a future stop?

M. Vercauteren and C. Susanne

Abstract Changes such as an increase in stature, in weight and an earlier physical and sexual maturation have been observed since the 19th century in Belgium as in most industrialized countries.

In this paper, we consider the secular trend in height, weight and puberty (especially menarche) over the last 20 years in Brussels. During the period 1980–1982, 4177 subjects, from the Belgian population of Brussels, aged 3–26 years, have been measured and compared with Belgian subjects living in Brussels in 1960.
In our sample, we observe a statistically significant increase in height (and weight), but this trend is less rapid than the increases noticed before in Belgium.
Status quo data on menarche from 1048 girls from this sample were analysed by centiles and the probit method. For the first time in Belgium, it seems that the median age is stabilized at 13.0 years. However, the number of late menarches is still evolving.

Menarche Portugal

Age at menarche in Coimbra (Portugal) school girls: a note on the secular changes
C. Padez and M. A. Rocha

Summary. The age at menarche and several menstrual symptoms were reported by 516 Portuguese school girls who took part in a cross-sectional anthropometric study in Coimbra, Portugal. The mean ages of menarche calculated using the recall method and also using probit analysis were 12.53 1.27 and 12.03 1.26 years, respectively. Parents’ educational level, place of residence and size of the family did not have any significant effect on the mean age at menarche in this sample of adolescents. The order of birth was the only variable that indicated a significative effect: the firstborns reported a lower mean age at menarche (12.34 years) than the later borns (12.6 years). In this sample, 47% of the girls had a cycle length of 529 days, 23.4% had irregular cycles, 59% reported that the duration of bleeding was 3–5 days and the majority, 49%, did not report any pain during the bleeding days. However, 14.3% and 24.45% reported severe and medium pain. The age at menarche has declined from 15.0 (girls born in 1880–1890) to 12.03 (girls born in 1970–1980) years in the Portuguese population. This decrease in age, and also the lack of influence of the family characteristics, appear as a result of the great improvements in the social and economic living conditions that occurred in Portugal, especially after the 1970s. These improvements are mainly related to better nutrition and better health care along with many other environmental factors.

France Menarche

"This study compares all calculable means of a new 1974 sample of
3,355 French women ages 17 to 21 with earlier available results, which
indicates a decrease in age at menarche in France and at the same time
a decrease in variance since the last centruy. Plotting all samples
available, the results of equations of linear regression indicate a
decreasing age in France at the rate of -.175 years/decade. ...
Although the rate in France of -.175 seems slower than reported, in
general, .3 years/decade, it is noted that the mean age in France in
the middle of the last century, reported to be 16 or 17, was less than
ages reported in Northern Europe. "

Ducros, A. The trend toward earlier menarche in France. Journal of
Human Evolution. 1981;10(8):623-25.

Evolution of age at menarche and at onset of regular cycling in a large cohort of French women F. Clavel-Chapelon,1 the E3N-EPIC group

Human Reproduction, Vol. 17, No. 1, 228-232, January 2002

BACKGROUND: Early exposure to ovarian hormones is considered to increase breast cancer incidence. The age at which the ovaries become functional is thus important. METHODS: We explored the evolution of age at first menstruation and at onset of regular cycling in 86 031 women participating in the E3N-EPIC cohort study, part of the European Prospective Investigation into Cancer. RESULTS: We observed an increase in mean age at menarche among women born between 1925 and 1930, followed by a steady decrease in the youngest birth cohorts. In contrast, age at onset of regular cycling increased gradually from 1925 onwards. There was thus a steady increase in the interval between age at menarche and at onset of regular cycling, mainly due to an increase in the percentage of women in whom regular cycling started at least 5 years after menarche (from 9.0% among women born in 1925–1929 to 20.8% in those born in 1945–1950). The increase in the interval between menarche and onset of regular cycling was even greater among women with a late menarche. CONCLUSIONS: This increase might be due to a change in dietary intake and/or physical exercise aimed at achieving the slim silhouette desired by the younger generations.

Norway Menarche

"age at menarche fell from just above 16 years for women born around
1830 to just above 13 years for those born around 1960"

Rosenberg M. Menarcheal age for Norwegian women born 1830-1960. Ann
Hum Biol. 1991 May-Jun;18(3):207-19.

Menarcheal age for Norwegian women born 1830-1960.

Data from birth records from the maternity hospitals in the three main cities in Norway have been used to study the trend in menarcheal age for women born from about 1830 to about 1960. The investigation is based on a sample of 200-300 records around every 10th year from each of the three clinics in partly overlapping time periods relating to a total of 9152 women. The recollected age at menarche fell from just above 16 years for women born around 1830 to just above 13 years for those born around 1960, the decrease being not totally linear. These results correspond closely with a previously published investigation from Oslo from about the same period of time (Brudevoll, Liestol and Walloe, 1979), but our results, which cover more of Norway, show a more linearily shaped curve than the results covering only Oslo. We have also analysed the relationships of several independent variables to menarcheal age, using multivariate linear regression methods. Besides the woman's year of birth, which was the most important variable throughout the whole period of time, various geographical variables were found to be of moderate importance. Being born in the countryside and in towns other than Oslo and Bergen led to a slightly higher age at menarche. No significant difference between Oslo, Bergen and Trondheim was detected except for the period up to about 1880 where the Bergen women had about 2.6 months earlier menarche than the Oslo women. Married women amongst the sample had experienced menarche a little earlier than the unmarried, and among married women there was an association between occupation and menarcheal age, women from the lowest social classes having the latest ages at menarche. The importance of these socially related parameters declined with time, and for women born after 1945 the difference seemed to have disappeared. The age at menarche was found to be positively related to a woman's age at first birth; the further back in time the stronger the relation. In addition, delayed age at menarche was also found to be associated with irregularities in the menstrual cycles in later life.

Puberty and Adolesence

This power point presentation is fascinating. At least someone is thinking!

Japan Menarché

There is this early article from 1981:

Secular trend of the age at menarche of Japanese girls with special regard to the secular acceleration of the age at peak height velocity.

Hoshi H, Kouchi M, Hum Biol. 1981 Dec;53(4):593-8.

PIP: An attempt is made to clarify the special characteristics of the secular trend of the menarchial age in Japan. The relationships with the precocious appearance of the age at peak high velocity, another exemplification of the maturity acceleration, is also reviewed. This research on menarche was conducted in 1979-1980 on 284 school girls born between 1961 and 1966. The girls were healthy, of middle socioeconomic class, and grew up and lived in Tokyo and its outskirts. A questionnaire was given to each subject who was requested to answer after referring to her diary, mother's or sister's records, or any other writing about her menarche. If none of these was available, they were asked to provide an event which occurred soon before or after the menarche. The arithmetic mean of the age at menarche was 12.40 years with a range of 9.63 to 15.44 years. In 1958 research was conducted on the menarche of 309 girls in the same school, and the mean menarchial age was reported to be 13.27 years with a range of 10.83 to 16.92 years. The rate of acceleration during these 21 years was 4.4 months/decade. Mean menarchial ages obtained in 157 studies ever reported in Japan were plotted against the year of publication. No definite tendency was apparent until a gradual change toward earlier menstruation began in about 1920. In the next 20 years the average decreased from 15.0 to 14.2 years of age. The rate of decrease during the 1920-1940 period was about 4 months/decade. Due to World War 2, a retardation of menarche began in 1941 and reached a peak of about 15.0 years of age in 1950-1952, after which the trend changed into one of rapid acceleration. It is believed that the age at peak height velocity (PHV) is highly correlated with menarche age. The correlation coefficient is reported to be 0.71 by Nicholson and Hanly (1953), 0.93 by Deming (1957) and 0.77 by the author's of this study based on the present subjects. Thus it can be reasonably assumed that the secular trend of menarche must be associated with a similar trend for PHV age.

Menarche in S Korea

"South Korean women born between 1920 and 1986... Mean menarcheal age
decreased from 16.8 to 12.7 years during the past 67 years."

Hwang JY, Shin C, Frongillo EA, Shin KR, Jo I. Secular trend in age at menarche for South Korean women born between 1920 and 1986: the Ansan Study.Ann Hum Biol. 2003 Jul-Aug;30(4):434-42.

BACKGROUND: There is strong evidence of a downward secular trend in age at menarche in Europe and the USA during the last century and in Japan and China during the past few decades. However, no study on this trend in age at menarche has been reported in South Korea. AIM: To measure the trend in age at menarche in South Korea during the past few decades and the association of height with this trend. SUBJECTS AND METHODS: A total of 1061 South Korean women born between 1920 and 1986 were randomly recruited from Ansan Cohort Study samples and separate school girl samples, and subjected to this analysis. The data on age at menarche were collected by the retrospective method. Height was measured at time studied and assumed to be relatively constant since age at menarche. Women were grouped with respect to decade of birth and mean age at menarche was determined. The secular trends in annual age at menarche and in height were analysed by the 3-year moving average. RESULTS: Mean menarcheal age decreased from 16.8 to 12.7 years during the past 67 years, corresponding to -0.64 years per decade. Height increased from 149.23 to 161.75 cm during the same period, showing an inverse relationship in the change of trend between height and mean age at menarche. CONCLUSION: Our data suggest that the downward secular trend in age at menarche may reflect the secular change in physical growth in South Korean women during the past 67 years.

Edward Frongillo at Cornell

Menarche in Brazil

Family socio-economic background modified secular trends in age at menarche: evidence from the Pro-Saude Study (Rio de Janeiro, Brazil).
Junqueira Do Lago M, Faerstein E, De Souza Lopes C, Werneck GL; Pro-Saude Study (Rio de Janeiro, Brazil)
Ann Hum Biol. 2003 May-Jun;30(3):347-52


BACKGROUND: Since age at menarche has been associated with socio-economic status, its downward secular trend might vary according to the different socio-economic status levels of the family in which women lived during their childhood. AIM: This study seeks to describe secular trends in age at menarche for Brazilian women whose fathers had different levels of educational attainment. SUBJECTS AND METHODS: A self-administered questionnaire was applied to 2053 women born between 1931 and 1977. Multiple linear regression models were employed to estimate trends in age at menarche according to categories of educational level of the participants' father. RESULTS: The age at first menstruation varied from 7 to 19 years, with a mean age of 12.3 years (+/- 1.64 SD). The reduction in age at menarche was 2.4 months per decade for all women. Among daughters of fathers with less than 8 years of schooling this reduction was 3.6 months per decade, and among daughters of fathers with 8 years or more of study it was 1.2 months per decade. CONCLUSION: Improvements in living conditions in Brazil over the last decades seem to have had a stronger effect on the reduction of the age at menarche among women who lived their childhood in worse socio-economic standards.

The aggregate data (with a mean reduction of 2.4 months per decade) reveal little difference from the 1 year per 45 years for the developed world, the faster rate for poorer families (3.6 months per decade, which is nearer 1.5 years per 45, could be significant. It depends.