Fetus is a possible target of preemptive medicine—from curative endocrinology to preemptive endocrinology—

Introduction

In celebration of the 100^th anniversary of The Japan Endocrine Society, I wish to refer and summarize the past development of human biology, especially in the field of reproductive endocrinology. I am very happy that I can refer Japanese medical scientist at the beginning of this remark. In 1920, Japanese scientist Dr Hirose T reported ovulation and normal luteal function in immature rabbits by repeated injections of human placental tissue [1], indicating that there was a clear hormonal link between the placenta and ovarian functions, including ovulation and steroid hormone production. This finding was followed by the famous demonstration by Dr Aschheim S and Dr Zondek B in 1927 in which pregnant women produced a gonad-stimulating substance [2], named later as human chorionic gonadotropin (hCG). This system was named as “Zondek-Ascheim pregnancy test” and used as long as 30 years in the clinical practice. This pregnancy test has evolved into a sensitive assay kit detecting urinary hCG as low as 25 IU/L, which is similar to that in the women 2 weeks after fertilization of the egg. Thus, at present, women are able to notice their pregnancy as early as four weeks of pregnancy, when the gestational sac, an indicator of clinical pregnancy, is undetectable yet by any sensitive ultrasonography instrument.

1. Perinatal Endocrinology

1) Progress in assisted reproductive technology (ART)

Numbers of findings in the field of reproductive endocrinology such as uterine endometrium and fertilization as well as implantation of embryo have been accumulated by the late 70’s of 20^th century. As a clinical application of these findings, Drs. Edwards RG and Steptoe PC facilitated the birth of Louise Brown in 1978 using in vitro fertilization and embryo transfer (IVF-ET) technology [3]. Forty five years later, this IVF-ET technology is widely applied to infertile couples and nowadays 8 % of newborns are born from this assisted reproductive technology (ART). Thus, the main topics of reproductive endocrinology of 20^th century were discoveries of hormones and substances which regulate various functions of reproductive organs, and the application of this knowledge to the diagnosis and treatment of conditions such as ovulation failure or infertility. The final product of development in reproductive endocrinology was the establishment of ART and its routine application in the clinical treatment of infertile couples.

2) Initiation of parturition

The duration of pregnancy varies depending on the animal species, and labor does not occur when the fetuses are immature. Thus, it is supposed that the uterus is in a state of quiescence under the control of some unknown mechanisms, while the fetus is immature. Then, parturition is initiated when the fetus becomes mature and ready to survive in the extra-uterine environment. These facts suggest that there may be some relation between fetal maturation and initiation of parturition. From this view point, it might be an attractive concept that the fetus and its accessories produce and secrete some bioactive substances as signals, and contribute to the formation or modulation of the intrauterine environment, which regulates both fetal growth as well as the initiation of parturition. Thus, an adequate intrauterine environment is necessary for normal fetal development. Conversely, physical and biochemical signals released from developing fetus relate closely to the initiation of parturition and removal of the conceptus from the mother. We investigated human parturition from this view point.

Contraction of the uterine myometrium is strictly regulated by calcium ions. Calcium ion uptake into myometrial cells is inhibited by cAMP which is produced by sequential actions of cyclooxygenase 1 (COX-1) and prostacyclin synthase (PGIS) in the myometrium. The activities of these enzymes (COX-1 and PGIS) are enhanced by estradiol which increases in the maternal plasma during pregnancy [4]. Another modulator of cellular calcium ion is cGMP, which is produced by the action of brain natriuretic peptide (BNP) secreted from amnion cells [5, 6] and inducible nitric oxide synthase (iNOS) in the uterine myometrium [7]. Human uterine myometrium expresses receptor for BNP guanylate cyclase, suggesting the physiological significance of high concentrations of BNP in the amniotic fluid during mid–pregnancy [8]. BNP levels in the amniotic fluid decreases at term. Fig. 1 illustrates the contribution of cAMP and cGMP secreted from the pregnant myometrium or fetal amnion cells to the formation of uterine quiescence and maintenance of pregnancy.

Fig. 1

Quiescence of pregnant uterine myometrium induced by prostacyclin, nitric oxide and brain natriuretic peptide (BNP) (Hypothesis)

The production of prostacyclin and nitric oxide in the myometrium is enhanced by estradiol secreted from placenta. BNP secretion increases during early and middle pregnancy but decreases at term. Thus, uterine quiescence is established in mid-pregnancy and diminishes at term.

Plasma levels of prostaglandins significantly elevate when labor commences at term. Prostaglandin F_2α has potent contractile activity on uterine smooth muscle and causes the onset of labor, which is characterized by repeated cycles of contraction and relaxation of the uterine smooth muscle. The predominant precursor of prostaglandin F_2α synthesis by cyclooxygenase-1, 2 (COX-1, 2) is arachidonic acid, which is released from phospholipids in the amnion and decidua membranes by the sequential actions of phospholipase A₂ (PLA₂) [9], phospholipase C (PLC) [10], phospholipase D (PLD) [11] and diacylglycerol lipase (DGL) [12, 13]. PLA2 and PLC activities are dependent on calcium ion but PLD and DGL are not. PLA2 and PLC show substrate specificity. These enzymes are present in human amnion and decidua cells, and their activities are elevated at term.

When fetus grows up to fill the uterine cavity, the fetal presenting part, usually the fetal head, descends into the pelvic cavity, and extends the lower uterine segment and uterine cervix. This provokes weak irregular uterine contractions and causes cyclic mechanical stretch of the lower uterine segment and uterine cervix. Cyclic mechanical stretch enhances phospholipase A₂ expression and prostaglandin production by cyclooxygenase-2 (COX-2) in the lower uterine segment and adjacent fetal membranes [14].

Matrix metalloproteinase-1 (MMP-1) and elastase are believed to play important roles in the degradation of the extracellular matrix of the uterine cervix during parturition [15]. Leukocyte infiltration into the cervix is a characteristic feature of parturition. The mRNA expression and protein secretion of both interleukin-8 (IL-8) and monocyte chemotactic protein-3 (MCP-3) in cultured human uterine cervical fibroblast cells significantly increase after stimulation with cyclic mechanical stretch [16]. Thus, cyclic mechanical stretch by the presenting part of the developed fetus at term may initiate or facilitate cervical ripening through the augmentation of the production of IL-8 and MCP-3, followed by the infiltration of neutrophils and monocytes/macrophages, and increased secretion of MMP-1 and elastase in the uterine cervix, thus finally provokes the initiation of labor and the delivery of the fetus. Fig. 2 schematically illustrates the sequential reaction of cervical maturation and labor onset, triggered by cyclic mechanical stretch with the descending fetal head.

Fig. 2

Roles of cyclic mechanical stretch on the uterine cervix in the initiation of human parturition (Hypothesis)

Cyclic mechanical stretch enhances both maturation of uterine cervix and contraction of the uterine body through the sequential actions of various chemokines and prostaglandins.

3) Placental hormones and fetal growth

Fetal life entirely depends on oxygen and nutrient supply from the mother through the placenta, which is the most important component of the intrauterine environment. Advanced technology in medical biology has offered us opportunities to investigate not only the placenta but also the human fetus as targets of medical research. One prominent progress was ultrasound technology, which provided us tools to evaluate fetal growth, development and functions in utero. Another progress was technology of molecular biology, which introduced many substances with biological functions into the field of reproductive science.

Dramatic changes in energy metabolism are well recognized in pregnant women. Increased food intake, decreased insulin sensitivity, and hyperlipidemia are major features of maternal metabolism during pregnancy. These changes are beneficial for providing energy to the fetus and preparing the mother for nursing. It is proposed that maternal adaptation to the pregnant state is mainly due to placental hormones, such as prolactin, placental lactogen, and steroid hormones.

Leptin was initially introduced as an adipocyte-derived messenger of energy metabolism [17]. Subsequently, we revealed that leptin is produced in the human placenta and secreted into both maternal and fetal circulations (Fig. 3) [18]. Since the leptin receptor is abundantly expressed in various maternal tissues, placenta, and fetal tissues, leptin is expected to play physiological and pathophysiological roles in pregnancy. Resistin, another adipocyte-derived peptide hormone, regulates insulin resistance and the development of type II diabetes mellitus. We found that resistin is expressed in the human placenta, and its expression in this tissue is higher than that in adipose tissue [19]. Thus, it is plausible that placenta-derived resistin has physiological significance in the regulation of maternal glucose metabolism by decreasing insulin sensitivity during human pregnancy. We also reported increased leptin production in trophoblast cells in pregnancies with certain pathological conditions, such as molar pregnancy [20], preeclampsia [21], and fetal growth restriction [22]. Plasma leptin levels in pregnant women with severe preeclampsia were significantly higher than those in BIM-matched control pregnant women without preeclampsia, although plasma leptin levels in women with mild preeclampsia were similar to those in BMI-matched normal pregnancies [21]. Leptin also plays a critical role in reproductive function as ob/ob mice, which lack the leptin gene, do not ovulate and are infertile. In contrast, leptin over-expressed transgenic mice exhibited premature menarche and had normal pregnancies [23]. Thus, leptin plays central roles in various reproductive processes [24]. Fig. 3 schematically illustrates the metabolic and reproductive activities of leptin and resistin from maternal adipose tissue and the placenta.

Fig. 3

Possible functions of placental leptin and resistin (hypothesis)

Human placental trophoblast cells produce both leptin and resistin. They are secreted into both maternal and fetal circulations, suggesting a possibility that they serve as potent modulators of maternal energy metabolism and fetal growth through their various functions on maternal and fetal peripheral organs and the hypothalamus.

4) Maternal hyperglycemia and fetal outcomes

Fetal growth is solely dependent on the maternal nutrient supply, in which glucose is the main and critical nutrient for fetal growth and development. Hyperglycemia, such as due to maternal diabetes mellitus, causes short-term effects on fetal growth or development, such as giant baby or fetal congenital anomalies. Specifically, the effects of hyperglycemia in the early stages of pregnancy, during the period of fetal organogenesis, are serious and can cause miscarriage, intrauterine fetal death, or fetal anomalies such as anencephaly, polydactyly, syndactyly, etc. We investigated the mechanism of such toxic effects of hyperglycemia from the viewpoint of oxidative stress using a mouse model with streptozotocin (STZ)-induced diabetes mellitus (DM). Thioredoxin (TRX) expresses widely in the body and has potent anti-oxidative activity. TRX-overexpressing transgenic (TRX-Tg) male mice were mated with wild-type STZ-induced DM female mice. In the uterus of these pregnant DM mice, both TRX-Tg and wild-type fetuses co-exist and are affected equally by the oxidative stress of hyperglycemia (300 mg/dL). The incidences of major anomalies such as encephalocele and omphalocele were higher in the wild-type fetuses than in the TRX-Tg fetuses. In addition, 8-hydroxy-deoxyguanosine (8-OHdG), a marker of oxidative stress, and caspase-3, an indicator of apoptosis, were highly expressed in the central nervous system of the wild-type fetuses, but not in the TRX-Tg fetuses. These findings suggest that overexpressed thioredoxin suppressed apoptosis induced by the oxidative stress of hyperglycemia and blocked the occurrence of anomalies in the brains of the TRX-Tg mice [25].

We further examined the fetuses of TRX-Tg mice. In the placenta of the TRX-Tg mice, increased expression of 11βHSD-1 enhanced GLUT-1 expression, resulting in faster fetal growth compared to that of wild-type fetuses. At 4 weeks of age, the neonatal body weight, glucose tolerance test, and insulin secretion in TRX-Tg mice were the same as those observed in wild-type fetuses. However, at 10 weeks of age, the TRX-Tg group showed hyperglycemia due to insulin secretion deficiency. Such an early failure of pancreatic β cell function was thought to be related to the decreased expression of pancreatic Pdx-1, a transcription factor which regulates pancreatic differentiation [26].

2. Prenatal Environment and Health and Disease of Offspring in Later Life

1) Fetal programming -thrifty phenotype hypothesis-

Besides the brilliant successes of ART based on the accumulated knowledge of reproductive endocrinology and perinatal endocrinology, epoch-making findings have also been reported in the field of epidemiology during the same period. In 1976, Dr Ravelli GP reported that neonates exposed to severe famine during their fetal lives in the Dutch Famine under the occupation by German troops in 1944–1945 during the 2^nd World War, exhibited a higher risk of obesity 30 years later in their lives compared to control groups not exposed to the famine [27]. Ten years after this report, an English epidemiologist, Dr Barker DJ, investigated the regional distribution of deaths from cardiovascular disease in England and Wales, and found a significant correlation between the incidence of death from cardiovascular disease and that of neonatal death in the same districts [28]. Following these reports, many scientists investigated the relationship between fetal nutrition (birth weights) or neonatal nutrition and the risks of adult diseases later in life, such as obesity, impaired glucose metabolism, hypertension, hyperlipidemia, schizophrenia, etc. Based on the findings of these studies, the concept of the thrifty phenotype hypothesis was proposed, in which adult metabolic diseases are believe to originate not only from genetic and lifestyle factors but also from intrauterine environments such as poor or malnutrition (hyperglycemia) [29]. Maternal malnutrition, such as hyperglycemia or undernutrition, influences the fetus or newborn so as to prepare for malnutrition in their future lives, then they adapt and/or modulate their organ development to fit under- or hyper-nutritional condition. Finally, they develop their phenotypes such as insulin resistance, decreased β-cell function, renal failure, or hypertension. This concept is named as the “fetal programming hypothesis” or the “thrifty phenotype hypothesis” [29].

2) Mechanism of fetal programming by prenatal undernutrition

To elucidate further the mechanisms of fetal programming of adult disease by maternal undernutrition, we prepared a mouse model in which offspring with fetal undernutrition (UN offspring) developed on a high-fat diet (HFD) pronounced weight gain and adiposity, accompanied with impaired diet-induced thermogenesis [30]. UN offspring were born small but caught up in body weight to normal nourished offspring (NN offspring) within 10 days after birth. They showed no apparent difference in body weight and fat mass on a regular chow diet (RCD) thereafter. However, when fed an HFD since 8 weeks of age, UN offspring (UN + HFD) developed pronounced weight gain and adiposity compared to NN offspring on an HFD (NN + HFD).

We next examined changes in leptin expression in the adipose tissue during the neonatal catch-up growth period. Leptin mRNA expression in the subcutaneous adipose tissue from UN offspring was increased at 8 days of age compared to that from age-matched NN offspring. The onset of the leptin surge, a transient rise of serum leptin levels in mouse neonates, is reported to occur around 2 weeks of age [31, 32]. Surprisingly, the leptin surge occurred 8–10 days after birth in UN offspring, almost 1 week earlier compared to NN offspring (which typically occurs 16 days after birth). Thus, the leptin surge in UN offspring occurred during the period of catch-up growth. On the other hand, neonatal catch-up growth is reported to be closely associated with obesity in adulthood [32].

To examine whether premature leptin surge is associated with pronounced weight gain in UN offspring on an HFD, we induced premature leptin surge in NN offspring through the exogenous administration of leptin in the early neonatal period. During the treatment, NN offspring treated with leptin tended to gain less weight compared to the vehicle-treated groups, but the difference was not significant. Unexpectedly, the premature leptin surge generated by exogenous leptin administration led to pronounced weight gain on an HFD in NN offspring [30]. Both UN offspring and neonatally leptin-treated NN offspring exhibited an increased density of hypothalamic nerve terminals. Here, we postulate that the premature leptin surge alters energy regulation by the hypothalamus and is critical in the “fetal origins of obesity” [30]. This study was selected as a featured article of the journal “Cell Metabolism,” and the picture of pronounced obese mice on an HFD was presented on the cover page of that issue.

To further evaluate the essential involvement of early exposure to leptin in the developmental origins of obesity, we assessed the progression of obesity on an HFD in adulthood in leptin-deficient ob/ob male mice exposed to intrauterine undernutrition by maternal food restriction (ob/ob UN offspring) or to leptin treatment during the neonatal period, which is comparable to the premature leptin surge observed in the wild-type UN offspring [33]. On an HFD, the body weight of the male ob/ob UN offspring paralleled that of ob/ob offspring exposed to normal intrauterine nutrition (ob/ob NN offspring). In contrast, early exposure to exogenous leptin in ob/ob NN offspring during the early neonatal period reproduced the development of pronounced obesity on an HFD in adulthood. These findings indicate that early neonatal exposure to leptin, but not antenatal undernutrition, is associated with an aggravation of HFD-induced obesity in later life in the ob/ob background, thus supporting the concept that the premature leptin surge plays an essential role in the developmental origins of obesity [33]. Fig. 4 illustrates the role of premature leptin surge in obesity of mice offspring exposed to undernutrition in utero.

Fig. 4

Role of premature leptin surge in obesity of mice offspring exposed to undernutrition in utero

The premature leptin surge affects the neonatal hypothalamus, leading to leptin resistance and a reset of energy metabolism. This modulation of the hypothalamus is thought to be a central event in the impaired regulation of energy expenditure, ultimately resulting in obesity later in life. However, this mechanism has not been proven in humans.

As observed in epidemiological studies, undernutrition in utero is a risk factor for cardiovascular disorders in adulthood, along with genetic and environmental factors. The local expression of angiotensinogen and related bioactive substances has been demonstrated to play pivotal roles in cardiac remodeling, including fibrosis and hypertrophy. To clarify the possible involvement of the local cardiac angiotensin system in fetal undernutrition-induced cardiovascular disorders, we developed a mouse model of undernutrition in utero through maternal food restriction (30% restriction), in which offspring (UN offspring) showed an increase in systolic blood pressure at both 8 and 16 weeks of age (p < 0.01 for both) [34]. UN offspring at 16 weeks of age also exhibited perivascular fibrosis of the coronary artery (p < 0.05) [34] and cardiac hypertrophy (16 weeks, p < 0.01), concomitant with a significant augmentation of angiotensinogen (Ang; p < 0.05) and endothelin-1 (ET-1; p < 0.01) mRNA expression in the left ventricles. At 18.5 postcoitum days, mRNA levels of Ang, angiotensin-converting enzyme (ACE), and ET-1 in whole heart tissues of in utero undernourished fetuses were significantly elevated (p < 0.05 for all) [34]. These findings suggest that fetal undernutrition activates the local cardiac angiotensin system, which contributed, at least in part, to the development of cardiac remodeling in later life, in concert with the effects of genetic predisposition and lifestyle [34]. Fig. 5 schematically illustrates the hypothetical roles of catch-up growth in fetal programming of risks for lifestyle diseases in FGR fetuses exposed to undernutrition in utero.

Fig. 5

Fetal programming of risks for lifestyle diseases in FGR fetuses exposed to undernutrition in utero (hypothesis)

The catch-up growth of FGR fetus exposed to undernutrition in utero plays a critical role in the fetal programming of various lifestyle diseases later in life. This process is initiated by predictive adaptive responses based on individual genetic backgrounds and is ultimately modulated by lifestyle in adulthood. Accumulation of data from large-scale cohort studies is required before this hypothesis can be proven in humans.

FGR: fetal growth restriction, IGF: insulin-like growth factor

3. Paradigm Shift from Curative Medicine to Preemptive Medicine

1) Developmental origins of health and disease (DOHaD) theory

Drs. Gluckman PD and Hanson MA further developed the fetal programming hypothesis to explain the relationship between the prenatal fetal environment and the health status and disease susceptibility later in life [35]. According to their theory, the prenatal (fetal) environment regulates gene expression through epigenetic mechanisms, defining the newborn’s phenotype (birth phenotype). This process is influenced by predictive adaptive responses (PARs) and developmental plasticity mechanisms. After birth, newborns are exposed to extra-uterine postnatal environments. When the postnatal environment matches to that predicted in utero, newborns can survive healthily, but when the postnatal environment does not match (mismatch) their prediction, newborns will become at a higher risk of some specific non-communicable diseases (NCDs) in their later lives. Genetic constructs, recognized as genotypes, are the accumulation of selections and mutations from the origin of humans to the present. Epigenetic changes are the accumulation of effects from the reproductive environment in past generations. Fig. 6 schematically illustrates how genetic and epigenetic factors, along with prenatal and postnatal environments, interact to create a pathway to altered disease risk in adulthood [35]. According to this concept, they suggest that “We are living with the past” [35]. Based on these understandings, they propose the concept that the environment during the developmental period of organ function prescribes the health and disease susceptibility of the organ. This concept is now accepted as the “Developmental Origins of Health and Disease (DOHaD).”

Fig. 6

Possible interventions to prevent or restore disease risks in adulthood

This flow chart shows a general model of how genetic and epigenetic factors, along with prenatal and postnatal environments, interact to create a pathway to altered disease risks in adulthood.

Blue arrows and columns have been inserted to the original model to indicate possible interventions for preventing or restoring disease risk in adulthood.

2) Intervention to fetal programming of disease risk by maternal nutrition

The central concept of the DOHaD theory is developmental plasticity, whereby gene expressions are regulated, positively or negatively, by epigenetic mechanisms, depending on the environment of the developing fetus. Thus, susceptibility to NCDs later in life is programmed during fetal life in utero. However, this also means that programming can be modified to prevent the onset of NCDs if an unfavorable environment can be changed into a favorable one through specific interventions [35]. In other words, developmental plasticity further offers us the chance of preemptive medicine in which the fetal programming of specific disease risks could be corrected or prevented through appropriate interventions, if there is a full understanding of the mechanisms of individual programming.

This concept led us to search for intervention tools to prevent or modify the fetal programming of later disease risks. Protein is an essential nutrient for fetal growth, and branched-chain amino acids (BCAA) are noted to have anabolic actions. Therefore, we next investigated the effects of a maternal high-protein diet or BCAA-supplemented diet on fetal growth under the condition of maternal calorie restriction [36]. Pregnant mice were calorie-restricted (undernutrition: UN), using either a standard-protein diet (SP-UN group), a high-protein diet (HP-UN group), or a BCAA-supplemented diet (BCAA-UN group) to 70% of the control from 10.5 days post coitum (dpc) to 18.5 dpc. The control group was fed ad libitum with a standard-protein diet (SP-NN group). Fetal weights of SP-UN groups were significantly decreased compared to that of the SP-NN. However, the fetal weights of HP-UN and BCAA-UN were significantly higher by 5% and 4%, respectively, than those of the SP-UN, concomitant with the augmentation of the gene and protein expressions of IGF-I and IGF-II in the fetal liver [36]. A high-protein diet as well as a BCAA-supplemented diet partially improved fetal growth restriction caused by maternal calorie-restriction, suggesting their pivotal role in the amelioration of fetal growth restriction [36].

Epidemiologic studies have shown that in utero malnutrition is a risk factor for adult cardiovascular disease (CVD) [28]. As mentioned previously, offspring in a mouse model with 30% maternal caloric reduction showed a significant increase in systolic blood pressure (SBP) as well as in cardiac remodeling-associated morphological parameters such as cardiac enlargement and coronary perivascular fibrosis in adulthood [34]. Using a similar animal model, we further demonstrated that an increased level of protein supplementation during an undernourished pregnancy (high-protein diet; HPD) corrected for the development of CVD risk factors found in fetal undernutrition with less protein content (standard protein diet; SPD) [37]. In contrast, maternal ad libitum feeding with HPD resulted in a significantly elevated SBP and cardiac enlargement in offspring at 16 wks. Thus, appropriate maternal protein ingestion might partly protect against the development of CVD risk factors in offspring exposed to undernutrition in utero [37].

We next investigated whether or not isocaloric supplementation with BCAA to maternal food restriction can reverse the adverse developmental hypertension in offspring [38]. Pregnant rats were divided into four groups at 7.5 dpc: normally nourished (NN) and 70% undernourished (UN) groups with and without BCAA supplementation (NN-standard diet (SD), NN-BCAA, UN-SD and UN-BCAA groups). Compared with pups in the NN groups, those in the UN-SD group had significantly increased systolic blood pressure (SBP) at 8 and 16 weeks of age (p < 0.05). However, the elevation of SBP was not observed in offspring in the UN-BCAA group. Glomeruli number of offspring of the UN groups was significantly lower (p < 0.05) than that of the NN groups, independent of BCAA supplementation. Angiotensin II receptor type 2 (ATR2) mRNA and protein expression in the kidney was significantly augmented in the UN-BCAA group at 30 weeks of age. These results suggest that BCAA supplementation during maternal food restriction prevents developmental hypertension together with increased ATR2 expression in adult offspring kidneys [38].

3) From curative endocrinology to preemptive endocrinology

As Dr Gluckman indicated in his review article [35], “We are living with the past.” As illustrated in Fig. 6, we live with genes which are accumulated as the results of selections and mutations during millions of years since the appearance of humans on the earth. These genes are also accompanied with the epigenetic modifications repeated in the past reproductive regenerations. To date we treat various NCDs such as diabetes or hypertension after they become manifest. However, the accumulated findings of human epidemiological studies and animal experimental studies from the view point of DOHaD have revealed the possibility of preventing or reducing disease risks caused by unfavorable intrauterine prenatal environments through appropriate interventions at specific developmental stages. It is proposed that based on the knowledges to the precise mechanism, non-communicable diseases such as hypertension, diabetes mellitus, etc. can be approached before the disease become manifest, which is named as preemptive medicine [39]. Prevention of hypertension is a good example of preemptive medicine [40]. Thus, the application of biological knowledge to human health care has shifted from curative medicine to preemptive medicine. Possible timing and intervention methods are shown by wide blue arrows and light blue columns in Fig. 6, respectively.

On the other hand, there are reports on the effects of paternal factors on DOHaD phenomena. When male rats fed with a high fat diet were mated with female rats fed with a standard diet, their offspring became impaired glucose tolerance in their adulthood [41]. This fact suggests that some of the parental epigenetic changes can be transferred to their offspring via germ cells. Mechanisms of transfer of information about the parental environment over generations, as well as methods and effects of intervention are proposed [42]. Many mechanisms of transferring information about environmental experience can underlie inheritance across generations, including both genome-associated factors (e.g., covalent modifications of histones, miRNA, tsRNA, and DNA methylation) and genome independent factors (e.g., the microbiome) [42]. Sperm tsRNA contributes to the intergenerational transmission of paternal environment-induced predisposition to NCDs in offspring. Intervention methods reportedly include the effects of diet, exercise, postnatal care, and supplementations with methyl modulators such as folate, vitamin B12, betaine, etc. Therefore, pre-conception education is needed for not only women before pregnancy but also for their partners to prevent intergenerational transmission of parentally transmitted disease risks. Thus, both male and female partners before conception are the target of the preemptive intervention to prevent and/or lower the transgenerational transmission of disease risks.

Conclusion

The main topics of reproductive endocrinology in the 20^th century included the discoveries of various hormones regulating reproductive functions such as ovulation, fertilization, implantation, fetal growth, and delivery. Accumulated knowledge on these functions finally enabled us to give babies to infertile couples with assisted reproductive technology, such as IVF-ET [3]. On the other hand, careful observation of the relationship between fetal growth (fetal nutrition) and disease risks later in life revealed that risks for adult diseases were largely determined by unfavorable prenatal environments [27, 28], which led to the concept known as the “Developmental Origins of Health and Disease.” It is now conceivable that disease risks originating from unfavorable prenatal environment might be lowered by appropriate interventions at the appropriate developmental stages, suggesting the scientific background of the preemptive medicine [35]. We are at the dawn of preemptive endocrinology, and further human studies and animal experiments are required.

Acknowledgements

I sincerely appreciate professors John M Johnstone and Paul C MacDonald and Dr Takeshi Okazaki in Departments of Biochemistry, Obstetrics and Gynecology, University of Texas, South Western Medical Center at Dallas for their kind assistance when conducting my research activity in their institute. I also thank Drs Hiroaki Itoh and Shigeo Yura in Department of Obstetrics and Gynecology, Kyoto University, professor Kazuwa Nakao, in Department of Internal Medicine, Kyoto University and Dr Takashi Sugiyama in Department of Obstetrics and Gynecology, Mie University, as well as all other colleagues for their cordial cooperation when performing my research works cited in this review article. Most of these works were supported in part by Grants-in-Aid for the Scientific Research from the Ministry of Education, Science, and Culture, Japan and by grants from the Smoking Research Foundation.

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• 19   Yura  S,  Sagawa  N,  Itoh  H,  Kakui  K,  Nuamah  MA, et al. (2003) Resistin is expressed in the human placenta. J Clin Endocrinol Metab 88: 1394–1397.
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• 34   Kawamura  M,  Itoh  H,  Yura  S,  Mogami  H,  Suga  S, et al. (2007) Undernutrition in utero augments systolic blood pressure and cardiac remodeling in adult mouse offspring: possible involvement of local cardiac angiotensin system in developmental origins of cardiovascular disease. Endocrinology 148: 1218–1225.
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Biographies

Norimasa Sagawa

Honorary Member

Professor Emeritus, Mie University

Adviser, General Women’s Medical and Health Science Center, Rakuwakai-Otowa Hospital

E-mail: [e-mail]

Careers in JES

2017– Honorary Member

2013– Senior Councilor

2007–2011 Director (General Affairs)

1995– Councilor

1983– Member

Contributions to EJ

2011– Editor