Over-ripeness ovopathy

A challenging hypothesis for sex ratio modulation

P.H. Jongbloet

Department of Epidemiology and Biostatistics, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands Email: p.jongbloet{at}epib.umcn.nl


    Abstract
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 Abstract
 Introduction
 Common determination of sex...
 Accumulation of...
 Conclusion
 References
 
Current hypotheses do not explain the concerns about sex ratio modulation at conception, birth or during life, and particularly about sex ratio reversal, e.g. at very young or advanced maternal age, during ‘anovulatory seasons’, among those of low socio-economic status, or induced by specific lifestyles, etc. These modulations are explained by the introduction of the ovopathy concept and inherent preferential fertilization of non-optimally matured oocytes by Y-bearing sperm. Non-optimal development and implantation of male-biased fetuses results in perennial loss of non-optimal, male-biased fetuses before and after birth. Accumulation of conceptopathology in extreme conditions entrains an increasing male to female ratio and ultimately a decreasing one, i.e. an ‘inverted dose–response gradient’ or ‘dose–response fallacy’.

Key words: fetal loss conception/hypothesis/mortality/ovopathy/sex ratio


    Introduction
 Top
 Abstract
 Introduction
 Common determination of sex...
 Accumulation of...
 Conclusion
 References
 
The male to female ratio at conception, i.e. the primary sex ratio (PSR), is not 100:100, either in animals, or in humans. In the golden hamster, this ratio was found to be 180:100 at 3.5 days after mating, and before implantation, but the secondary sex ratio (SSR) at birth was 106:100 (Sundell, 1962Go). In rabbits, 122 XY karyotypes were found in 6-day-old blastocysts for every 100 XX karyotypes; at birth, the SSR had diminished to 105:100 (Shaver and Carr, 1969Go). In human embyros also, a disproportional loss of male-biased fetuses during gestation has been claimed: at the end of the second month, 151 male to 100 female fetuses were observed, in contrast to the end of the third month, where only 132 to 100 were observed (Kukharenko, 1970Go). This ratio is reduced at birth, and contemporarily it varies between 105 and 107 boys for every 100 girls (Smith, 2000Go).

Reduced survival of male progeny before and after birth is a general finding in mammals. Male-biased age-specific morbidity and mortality remain prominent during neonatal life, infancy, adolescence and adult life, i.e. the tertiary sex ratio (TSR); a gender equilibrium is reached around the fourth to fifth decade; thereafter, the number of men decreases to ~30:100 at 75 years of age and to 20:100 at 90 years, the so-called ‘gender gap’ (Hytten, 1982Go; Smith, 1989Go). This gap is attributed to differences in age-specific mortality rates for heart disease, cerebrovascular accidents, neoplasms, chronic obstructive pulmonary disease, motor vehicle accidents, suicide and homicide (Newman and Brach, 2001Go). Female advantage in longevity exists worldwide and transculturally, even among nuns and monks, and is not explained by the prevalent theories (Christensen and Vaupel, 1996Go).

Any hypothesis which purports to clarify the sex ratio modulation in animals and humans should rise to three challenges: (i) the unexplained approach to equal sex proportion at birth in specific conditions and to higher SSRs in others; (ii) the unexplained perennial loss of male-biased fetuses and individuals during their lifetime; and (iii) the unexplained sex ratio reversal in particularly extreme circumstances. A basic and unifying concept on determination of both the condition and sex of the conceptus will be advanced: optimal endocrine tuning of both oocyte maturation and cervical mucus liquefaction favours optimal progeny and equal sex proportions at the core of the fertile window of the menstrual cycle; at the extremes of this window, non-optimal hormonal modulation entrains both pathological- and male-biased progeny.


    Common determination of sex and condition of the conceptus
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 Abstract
 Introduction
 Common determination of sex...
 Accumulation of...
 Conclusion
 References
 
One of the most interesting aspects of recent research into assisted fertilization and embryo transfer is the growing insight that oocytes at ovulation differ in developmental competence. The pronuclear morphology is closely related to blastocyst formation and zygote quality and highly predictive for the rate of fertilization, implantation, development and pregnancy (Balaban et al., 2001Go; Montag et al., 2001Go). A 2-fold increase in neurological sequelae in children born after IVF, even after adjustment for low birth weight, has been attributed to deficient quality in the IVF process, particularly in the harvest of optimally matured oocytes (Strömberg et al., 2002Go).

Concurrence of both maturation and cervical liquefaction is modulated by estrogens before the mid-cycle. The meiotic progression and developmental competence of human oocytes during the highly critical period for formation and maintenance of epigenetic information are acquired during follicle formation (Schramm and Bavister, 1999Go). Cervical liquefaction of the mucus plug plays a pivotal role in the migration of the sperm (Moghissi, 1973Go). This concurrence facilitates equal access to optimally matured oocytes by X- and Y-bearing sperm at the core of the fertile window and, thus, full expression of the genetic potential of the gametes, which guarantees good embryo quality in either sex.

In contrast, non-optimal liquefaction of the cervical mucus, elicited by endogenous or exogenous disturbing factors, will facilitate differential migration (Broer et al., 1976Go). The head, length, perimeter and area in Y-bearing sperm are significantly smaller than in X-bearing ones, and their necks and tails are shorter (Cui, 1997Go). Fertilization by Y-bearing sperm, therefore, is more likly to occur by non-optimal liquefaction at the very beginning and the end of the fertile window of the menstrual cycle. This conforms to the well-known U-shaped probability of delivering male offspring vis-à-vis timing of insemination in animals and of the estimated ovulation date in humans: equal sex proportions at the time of ovulation versus the moderate rise in males before or after it (Harlap, 1979Go; James, 1996Go).

Concurrence of non-optimal maturation and non-optimal liquefaction during the receptive period will lead to preferential fertilization of non-optimally matured oocytes by Y-bearing sperm. Non-optimal maturation before and after ovulation in animals, i.e. over-ripeness ovopathy, promotes multiple ovulation, axial duplication, the impossibility to be fertilized, mis-implantation, prenatal loss and transitory retardation leading to developmental anomalies (Witschi, 1952Go; Mikamo, 1968Go; Mattheij et al., 1994Go). Deficiencies in organogenesis and differentiation of the various tissues and organ systems are the result. The pleiotropic nature of non-optimally matured oocytes and the teratogenic consequences will depend on the degree of molecular, biochemical and physiological processes in the oocyte, which encompass both nuclear and cytoplasm constituents. The intricate interplay of non-optimal oocyte maturation and genes will result in a complex pathogenesis of the resultant fetuses or individuals. This occurs incidentally in well-timed menstrual cycles, but more so in condtions of distorted hormonal tuning.

Preferential fertilization of non-optimally matured oocytes by Y-bearing spermatocytes is not only in line with one of James’ proposals (James, 1996Go), i.e. that maternal hormone profiles are responsible for reproductive disorders that may produce an excess of one gender over another. It also elucidates the underlying developmental relationship between both sex determination and associated anomalies, such as the following

(i) The analogous U-shaped probability of increasing spontaneous abortions related to conceptions at the very beginning and at the very end of the fertile window versus reproductive success of those at the mid-cycle (Guerrero and Lanctot, 1970Go).

(ii) The male bias among adverse fetal outcome with chromosomal aberrations (Bishop et al., 1997Go), very early fetal loss (Källén et al., 1994Go; Mizuno, 2000Go), placental dysfunction (James, 1995Go; Edwards, 2000Go), preterm delivery (Cooperstock et al., 1997Go), stillbirths, developmental defects and ‘innate’ morbidity or early mortality in infancy and adulthood (Newman and Brach, 2001Go).

(iii) The male-biased perinatal mortality rate in same- and non-same-sex twin pairs, particularly in monozygotes (Rhydhström, 1990Go).

(iv) The increasing SSRs and pregnancy loss (smaller litters) in animals at very young and advanced maternal age, versus rather equal sex proportions and optimal progeny during ‘prime reproductive age’, independently of birth order and paternal age (King and Stotsenburg, 1915Go; Clutton-Brock and Jason, 1986Go; Kojola and Eloranta, 1989Go). The former conditions are characterized by an irregular ovulation rate, the latter by a regular one. Similar tendencies are known in humans, although often confounded by other determinants (see later).

(v) The high SSRs and adverse progeny at the breakthrough and breakdown of the ovulatory pattern in animals, versus optimal progeny and equal number of male and female births when mating occurs at the peak(s) of a seasonally determined heat period (Heape, 1908Go; King and Stotsenburg, 1915Go; Coulson and Hickling, 1961Go; Stirling, 1971Go; Lambin, 1994Go). These transitional stages of breeding and non-breeding seasons in female horses and rhesus monkeys are characterized by intermediate or low estrogen and progesterone levels (Freedman et al., 1979Go; Snyder et al., 1979Go; Walker et al., 1984Go). The existence of analogous alternating ‘ovulatory’ and ‘anovulatory’ seasons in humans is in line with the earlier recognized basic animal rhythm (Huntington, 1938Go) and was the basis for the seasonally bound pre-ovulatory over-ripeness ovopathy (SPrOO) hypothesis. The zeniths of the conception rate were the basis for the seasonally-bound optimally ripened oocytes (SOptRO) hypothesis (Jongbloet, 1975Go, 1986, 1990, 1992). The increase of conceptions related to perinatal mortality (corrected for pregnancy duration) and to high SSRs corresponds to the slopes of the seasonally determined peaks; those related to neonatal survival and equal sex proportions to the zeniths (see Figures 1a and b, and 2) in line with these hypotheses.




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Figure 1. Comparison of the risk of conceptions resulting in perinatal death corrected for pregnancy duration (per 1000 births) with the presumed daily singleton conception rate per month in 1973 in (a) Sweden and (b) Cuba (data from Golding and Sunderland, 1990Go).

 


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Figure 2 Comparison of the indexed birth frequencies of male and female live births with the SSR per month in Quebec in the 17th and 18th century (data from Nonaka et al., 1991Go). See text.

 
(vi) The increasing odds of delivering both a male child and progeny with developmental defects when the socio-economic level decreases from high to moderate (Teitelbaum and Mantel, 1971Go; Rostron and James, 1977Go). The gonadal function in animals and humans is strongly affected by deficient caloric intake, as reflected by the length of the menstrual cycle, in particular its pre-ovulatory phase (Reichman et al., 1992Go; Wynn and Wynn, 1993Go). The well-known secular increase of the SSRs before the First and Second World Wars in industrializing countries and of perinatal mortality and developmental defects has been explained by improvements in nutritional standards, general health and safer family planning, in other words by a decrease of the conceptopathology rate; the peaking of the SSRs around the First and Second World Wars and the subsequent downward trend in them by the same decrease and, thus, dcreasing male proportions and better male survival (see Jongbloet et al., 2001Go).

(vii)The male-biased attrition by chronic ‘innate’ diseases more severely and at younger age e.g. by type 2 diabetes mellitus (Barendregt et al., 2000Go), cardiovascular diseases (Price and Fowkes, 1997Go), schizophrenia and personality disorders (Rosenthal, 1970Go; Bardenstein and McGlashan, 1990Go), etc., explains the gender equilibrium in these patients earlier reached than at population level.


    Accumulation of conceptopathology, ‘vanishing male fetuses’, SSR reversal or ‘dose–response fallacy’
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 Abstract
 Introduction
 Common determination of sex...
 Accumulation of...
 Conclusion
 References
 
Increasing delay of insemination in rabbits, i.e. accumulation of conceptopathology, appears to entrain a dose–response gradient of an increasing proportion of male blastocysts and births, and after having surpassed a critical delay, a decreasing proportion or sex ratio reversal (Hammond, 1934Go; Shaver and Carr, 1969Go). This twist from high to low SSRs thus occurs in the case of more extreme dose exposure and inherent male-biased attrition at conception, disproportional mis-implantation, and loss of fetuses, i.e. ‘vanishing male fetuses’—in analogy with the phenomenon of ‘vanishing twins’. This is not a theoretical construction to explain the epidemiological findings, as suggested by dissenting opponents, but it corresponds to ‘distortion by differential prenatal loss’ or ‘inverted dose–response gradient’ put forward by Khoury et al. (1989Go, 1992) or to a ‘dose–response fallacy’ proposed by Selevan and Lemasters (1987Go).

SSR reversal below the 100:100 level cannot be explained exclusively by ovopathy, but needs an additional mechanism, e.g. interaction with deleterious sublethal X-linked genes—in males not compensated for by normal genes on the X-chromosome and worsening the destiny of XY fetuses (Smith, 1989Go). Mutations in principle run randomly and independently of periconceptional conditions, and a combination of both phenomena seems plausible as fetuses compromised by ovopathy will all the more be lost.

A ‘dose–response fallacy’ elucidates many inconsistencies in the progeny of animals (see Clutton-Brock and Jason, 1986Go) and spurious controversies in human epidemiological data, e.g. the worrying shifts in the female direction: (i) after an extended pre-ovulatory phase (Weinberg et al., 1995Go); (ii) after artificial insemination when preceded by the stress caused by ovulation induction procedures (Guerrero, 1970Go; James, 1985Go, 1996); (iii) after severe periconceptional life events, such as an earthquake (Fukuda et al., 1998Go; Hansen et al., 1999Go); (iv) after psychological tensions due to bombing raids in war situations (Ansari-Lari and Sadaat, 2002Go; Zorn et al., 2003Go); and (v) after parental periconceptional smoking (Fukuda et al., 2002Go) or dioxin contamination (Jongbloet et al., 2002Go).

These SSR reversals in the female direction were often (if looked at) associated with increased pregnancy loss or with reduction in fertility (Fukuda et al., 1998Go; Zorn et al., 2003Go). and apparently depend on the site and degree of attrition along the neuroaxis in spontaneously aborted or pregnancy-terminated fetuses with neural tube defects: 13:100 for high thoracic and cervical involvement, versus 375:100 for low spinal lesions involving the sacrum (Little and Elwood, 1991Go; Källén, 1994Go; Seller, 1995Go).

This highly female-skewed SSR observed in extreme conditions is in line with observational epidemiology in animals and humans. (i) At extremely young and advanced reproductive age in animals (see Clutton-Brock and Jason, 1986Go; Kojola and Eloranta, 1989Go). In humans, this drop is also conspicuous, often greatly compounded by an increase of other conceptopathology due to, for example, unplanned and unwanted conceptions, irregular coital frequency, a particular lifestyle (drugs and smoking), etc. (ii) At the troughs between the descending and ascending slopes of the birth peaks in animals (Wolda, 1935Go), as also occurs in humans (Jongbloet et al., 1996Go). The peak of perinatal mortality (see Figure 1a and b) and the drop in male/female ratio (see Figure 2) correspond to maximization of non-optimal maturation of the oocytes during the ‘anovulatory seasons’. (iii) After an essential fatty acid-deficient diet in female mice associated with a markedly reduced litter size, almost completely attributable to the number of male pups (Rivers and Crawford, 1974Go). The SSR reversal in the lowest socio-economic strata (Teitelbaum and Mantel, 1971Go; Rostron and James, 1977Go) and in countries before the demographic transition (Jongbloet et al., 2001Go) as well as the social patterning of developmental anomalies, perinatal, infant and adult morbidity or mortality have also been explained by gradual accumulation and exposure to conceptopathology. Conversely, the increasing SSRs and decreasing rates of developmental defects and morbidity when the family socio-economic level improves are due to decreasing exposure and, hence, increasing rates of optimally matured and fertilized oocytes, i.e. less male-biased fetal loss and, thus, more male survivors. Low socio-economic strata are related to more menstrual cycle disorders, abnormal body mass index, lower standards of nutrition, more smoking and use of drugs, and of unsafe methods of contraception resulting in more unplanned and unwanted pregnancies in the lowest socio-economic strata (see Jongbloet et al., 2001Go).


    Conclusion
 Top
 Abstract
 Introduction
 Common determination of sex...
 Accumulation of...
 Conclusion
 References
 
The ovopathy concept explains three enigmatic phenomena: (i) the male excesses at conception (PRS) and at birth (SSR); (ii) the perennial decreasing sex ratios during pregnancy and male bias in ‘innate’ morbidity and mortality in infants and adults; and (iii) the increasing gender gap in senescence. Proof of the key assumptions would permit a reduction in overstated genetic determinism in developmental anomalies and ‘innate’ constitutional diseases. Birth size parameters apparently have long-term consequences for the occurrence of common diseases in adulthood. Given the lack of evidence for the ‘fetal origin hypothesis’, it may be time for a paradigm shift in favour of a ‘conception origin hypothesis’.


    References
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 Common determination of sex...
 Accumulation of...
 Conclusion
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Ansari-Lari M and Saadat M (2002) Changing sex ratio in Iran, 1976–2000. J Epidemiol Community Health, 56,622–623.[Free Full Text]

Balaban B, Urman B, Isiklar A et al. (2001) The effect of pronuclear morphology on embryo quality parameters and blastocyst transfer outcome. Hum Reprod 16,2357–2361.[Abstract/Free Full Text]

Bardenstein KK and McGlashan YTH (1990) Gender differences in affective, schizoaffective, and schizophrenic disorders. A review. Schizophr Res 3,159–172.[CrossRef][ISI][Medline]

Barendregt JJ, Baan CA and Bonneux L (2000) An indirect estimate of the incidence of non-insulin-dependent diabetes mellitus. Epidemiology 11,224–279.

Bishop J, Huether CA, Torfs Corey F and Deddens J (1997) Epidemiologic study of Down syndrome in a racially diverse California population, 1989–1991. Am J Epidemiol 145,134–147[Abstract]

Broer KH, Winkhaus I, Sombroek H et al. (1976) Frequency of Y-chromatin bearing spermatozoa in intrauterine postcoital tests. Int J Fertil 21,181–185.[ISI][Medline]

Christensen K and Vaupel JW (1996) Determinants of longevity: genetic, environmental and medical factors. J Intern Med 240,333–341.[CrossRef][ISI][Medline]

Clutton-Brock TH and Jason GR (1986) Sex ratio variation in mammals. Q Rev Biol 61,339–374.[ISI][Medline]

Cooperstock M, Herman AA, Land G et al. (1997) Very preterm twin birth: role of race and fetal sex. Paediatr Perinat Epidemiol 11,Suppl, 147.

Coulson JC and Hickling G (1961) Variation in the secondary sex-ratio of the grey seal Halichoerus grypus (Fab.) during the breeding season. Nature 190,281.

Cui KH (1997) Size differences between human X and Y spermatozoa and prefertilization diagnosis. Mol Hum Reprod 3,61–67.[Abstract]

Edwards A, Megens A, Peel M and Wallace EM (2000) Sexual origins of placental dysfunction. Lancet 355 203–204.

Freedman LJ, Garcia MC and Ginther OJ (1979) Influence of photoperiod and ovaries on seasonal reproductive activity in mares. Biol Reprod 20,567–574.[ISI][Medline]

Fukuda M, Fukuda K, Shimizu T et al. (1998) Decline in sex ratio at birth after earthquake. Hum Reprod 13,2321–2322.[Abstract]

Fukuda M, Fukuda K, Shimizu T et al. (2002) Parental periconceptional smoking and male:female ratio of newborn infants. Lancet 359,1407–1408.[CrossRef][ISI][Medline]

Golding J and Sunderland R (1990) Month and day of delivery. In Golding J (ed.), Social and Biological Effects on Perinatal Mortality. Vol III: Perinatal Analyses. WHO, Geneva, pp. 105–150.

Guerrero R (1970) Sex ratio: a statistical association with type and time of insemination in the menstrual cycle. Int J Fertil 15,221–225.[ISI][Medline]

Guerrero R and Lanctot CA (1970) Aging of fertilizing gametes and spontaneous abortion. Am J Obstet Gynecol 107,263–267.[ISI][Medline]

Hammond J (1934) The fertilisation of rabbit ova in relation to time. J Exp Biol 11,140–166.

Hansen D, Moller H and Olsen J (1999) Severe periconceptional life events and the sex ratio in offspring: follow up study based on five national registers. Br Med J 319, 548–549.[Free Full Text]

Harlap S (1979) Gender of infants conceived on different days of the menstrual cycle. N Engl J Med 300,1445–1448.[Abstract]

Heape W (1908) Notes on the proportion of the sexes in dogs. Proc Camb Philos Soc 14,121–151.

Huntington E (1938) Sex, season and climate. In Season of Birth. John Wiley & Sons, Inc, New York, pp. 192–214.

Hytten FE (1982) Boys and girls. Br J Obstet Gynecol 89,97–99.[ISI][Medline]

James WH (1985) Dizygotic twinning, birth weight and latitude. Ann Hum Biol 12,441–447.[ISI][Medline]

James WH (1995) Sex ratios of offspring and the causes of placental pathology. Hum Reprod 10,1403–1406.[Abstract]

James WH (1996) Evidence that mammalian sex ratios at birth are partially controlled by parental hormone levels at the time of conception. J Theor Biol 180,271–286.[CrossRef][ISI][Medline]

Jongbloet PH (1975) The effects of preovulatory overripeness of human eggs on development. In Blandau RJ (ed); Aging Gametes. Their Biology and Pathology. International Symposium, Seattle, 1973. Karger, Basel, pp. 300–329.

Jongbloet PH (1986) Prepregnancy care: background biological effects. In Chamberlain G and Lumley J (eds), Prepregnancy Care: A Manual for Practice. J Wiley & Sons Chichester, pp. 31–51.

Jongbloet PH (1990) Ovulation and seasons—vitality and month of birth. In Tomassen GJM, de Graaff W, Knoop AA and Hengeveld R (eds), Geo-cosmic Relations; The Earth and its Macro-environment. Proceedings, Pudoc, Wageningen, The Netherlands, pp. 143–156.

Jongbloet PH (1992) Seasonal fluctuation of pathological and optimum conceptions, maternal subfecundity, gender dimorphism and survival. Coll Anthropol 16,99–107.

Jongbloet PH, Groenewoud JMM and Zielhuis GA (1996) Further concepts on regulators of the sex ratio in human offspring. Non-optimal maturation of oocytes and the sex-ratio. Hum Reprod 11,2–7.[ISI][Medline]

Jongbloet PH, Zielhuis GA, Groenewoud HMM and Pasker-de Jong PCM (2001) The secular trends in male:female ratio at birth in postwar industrialized countries. Environ Health Perspect 109,749–752.[ISI][Medline]

Jongbloet PH, Roeleveld N and Groenewoud HMM (2002) Where the boys aren’t: dioxin and the sex ratio. Environ Health Perspect 110,1–3.[Medline]

Källén B, Cooohi G, Knudsen LB et al. (1994) International study of sex ratio and twinning of neural tube defects. Teratology 50,322–331.[ISI][Medline]

Khoury MJ, Flanders WD, James LM and Erickson JD (1989) Human teratogens, prenatal mortality and selection bias. Am J Epidemiol 130,361–370.[Abstract]

Khoury MJ, James LM, Flanders WD and Erickson JD (1992) Interpretation of recurring weak associations obtained from epidemiologic studies of suspected human teratogens. Teratology 46,69–77.[ISI][Medline]

King HD and Stotsenburg JM (1915) On the normal sex ratio and the size of litter in the albino rat (Mus norvegicus albinus). Anat Rec 9,403–419.

Kojola I and Eloranta E (1989) Influences of maternal body weight, age, and parity on sex ratio in semidomesticated reindeer (Rangifer t.tarandus). Evolution 43,1331–1336.[ISI]

Kukharenko VI (1970) The primary sex ratio in man (analysis of 1014 embryos). Genetika 6,142–149.

Lambin X (1994) Sex ratio variation in relation to female philopatry in Townsend’s voles. J Anim Ecol 63,945–953.[ISI]

Little J and Elwood JM (1991) Epidemiology of the neural tube defects. In Kiley M (ed), Reproductive and Perinatal Epidemiology. CRC Press, Boca Raton, Florida, 13,254–257.

Mattheij JAM, Swarts JJM, Hurks HMH et al. (1994) Advancement of meiotic resumption in Graafian follicle by LH in relation to preovulatory ageing of rat oocytes. J Reprod Fertil 100,65–70.[Abstract]

Mikamo K (1968) Intrafollicular overripeness and teratologic development. Cytogenetics 7,212–233.[ISI][Medline]

Mizuno R (2000) The male/female ratio of fetal deats and births in Japan. Lancet 356,738–739.[CrossRef][ISI][Medline]

Montag M and van der Ven H on behalf of the German Pronuclear Morphology Study Group (2001) Evaluation of pronuclear morphology as the only selection criterion for further embryo culture and transfer: results of a prospective study. Hum Reprod 11,2384–2389.

Moghissi KS (1973) Sperm migration through the human cervix. In Elstein M, Moghissi KS and Borth R (eds) Cervical Mucus in Human Reproduction. Scriptor, Copenhagen, pp. 128–152.

Newman AB and Brach JS (2001) Gender gap in longevity and disability in older persons. Epidemiol Rev 23,343–350.[ISI][Medline]

Nonaka K, Desjardins B, Charbonneau H, Légare J and Miura T (1991) Seasonality of general births and secondary sex ratio in the 17th and 18th century Canadian population. Triennial Rep 6,8–15.

Price JF and Fowkes GR (1997) Risk factors and the sex differential in coronary artery disease. Epidemiology 8,584–591.[ISI][Medline]

Reichman ME, Judd JT, Taylor PR et al. (1992) Effect of dietary fat on length of the follicular phase of the menstrual cycle in a controlled diet setting. Obstet Gynecol Surv 47,643–644.

Rhydhström H (1990) The effects of maternal age, parity, and sex of the twins on twin perinatal mortality. A population based study. Acta Genet Med Gemellol 39,401–408.[Medline]

Rivers JPW and Crawford MA (1974) Maternal nutition and the sex ratio at birth. Nature 252,297–298.[ISI][Medline]

Rosenthal D (1970) Genetic studies of schizophrenia (dementia praecox). In Genetic Theory and Abnormal Behavior. McGraw-Hill, New York, pp. 92–200.

Rostron J and James WH (1977) Maternal age, parity, social class and sex ratio. Ann Hum Genet 41,205–217.[ISI][Medline]

Schramm RD and Bavister BD (1999) A macaque model for studying mechanisms controlling oocyte development and maturation in human and non-human primates. Hum Reprod 14,2544–2555.[Abstract/Free Full Text]

Selevan SG and Lemasters GK (1987) The dose–response fallacy in human reproductive studies of toxic exposures. J Occup Med 29,451–455.[ISI][Medline]

Seller MJ (1995) Sex, neural tube defects, and multisite closure of the human neural tube. Am J Med Genet 58,332–336.[ISI][Medline]

Shaver EL and Carr DH (1969) The chromosome complement of rabbit blastocysts in relation to the time of mating and ovulation. Can J Genet 11,287–293.[ISI]

Smith DWE (1989) Is greater female longevity a general finding among animals? Biol Rev 64,1–12.[ISI][Medline]

Smith GG (2000) Sex, birth weight, and the risk of sillbirth in Scotland, 1980–1996. Am J Epidemiol 151,614–619.[Abstract]

Snyder DA, Turner DD, Miller KF, Garcia MC and Ginther OJ (1979) Follicular and gonadotrophic changes during transition from ovulatory to anovulatory seasons. J Reprod Fertil, Suppl., 27,95–101.

Stirling I (1971) Variation in sex ratio of newborn weddell seals during the pupping season. J Mammal 52,842–844.[ISI]

Strömberg B, Dahlquist G, Ericson A et al. (2002) Neurological sequelae in children born after in-vitro fertilisation: a population-based study. Lancet 259,461–465.

Sundell G (1962) The sex ratio before uterine implantation in the golden hamster. J Embryol Exp Morphol 10,58–63.[ISI][Medline]

Teitelbaum M.S. and Mantel N (1971) Socio-economic factors and the sex ratio at birth. J Biosoc Sci 3,23–41.[ISI][Medline]

Walker ML, Wilson ME and Gordon TP (1984) Endocrine control of the seasonal occurrence of ovulation in rhesus monkeys housed outdoors. Endocrinology 114,1074–1081.[Abstract]

Weinberg CR, Baird DD and Wilcox AJ (1995) The sex of the baby may be related to the length of the follicular phase in the conception cycle. Hum Reprod 10,304–307.[Abstract]

Witschi E (1952) Overripeness of the egg as a cause of twinning and teratogenesis: a review. Cancer Res 12,763–797.[ISI]

Wolda G (1935) Over de verhouding van mannelijke en vrouwelijke geboorten bij rund en varken. Landbouwk Tijdschr 47,420–425.

Wynn M and Wynn A (1993) No nation can rise above the level of its women. The Caroline Walker Lecture. The Caroline Walker Trust, London.

Zorn B, Sucur V, Stare J and Meden-Vrtovec H (2003) Sex ratios of births conceived during wartime. Hum Reprod 18,1134–1135.[Free Full Text]