The adrenal gland in the human fetus is proportionately much larger compared to the kidney than it is in the child or adult[1]. This increase in size is due to the fetal adrenal, a histologically distinct inner region that compromises over 80% of the gland and produces 16-OH-Dihydroepiandrosterone sulfate (DHEAS), the necessary precursor for the placental production of estrogen which is secreted into the maternal circulation. This fetal adrenal is a feature of primates but not of other mammals.
In the sheep, Liggins and colleagues discovered that the placenta has the enzyme, CYP17, which is absent in the primate placenta, and is necessary to convert cholesterol via pregnenolone into estrogen[2]. When the lamb hypothalamic axis matures, it stimulates cortisol production in the adrenal via ACTH. Cortisol induces organ maturation in preparation for birth, and up-regulates CYP17 resulting in increased maternal estrogen. The increasing ratio of estrogen to progesterone is the signal for myometrial cells to alter their phenotype via gap junctions, receptors and calcium channel modifications to produce labor. Why did primates abandon this simple mechanism of estrogen production for the more circuitous fetal adrenal function?
The speculative answer is that primates had large brains and needed to be delivered prior to full maturation of the brain. If not, the large infant head would become entrapped in the pelvis. Survival of the big brained primates would require the co-evolution of a way to deliver this big brain. The fetus needed to be delivered before the hypothalamic axis was fully mature, but cortisol would still be needed to mature other organs especially the immature lungs.
To deliver the big brained infant prematurely, cortisol production needed to be uncoupled from brain maturation. The primate may accomplish this uncoupling via corticotrophin releasing factor (CRF) produced in the placenta rather than from the mature hypothalamus[3]. This mechanism may have evolved originally to abort compromised pregnancies. For example if the placenta became relatively hypoxic, sending a placental generated CRF signal to the pituitary would increase ACTH and hence cortisol. This would initiate labor and result in the premature delivery of the fetus with the added benefit of a boost to its lung maturation. The spontaneous abortion of a compromised fetus might improve the mothers overall reproductive success. Even If we accept the speculation that the initiation of labor in the primate hijacked a local placental mechanism of CRF to initiate labor several weeks earlier than brain maturation would have, we still need a rationale for abandoning the placental production of estrogen. Placental CRF could still have initiated the cortisol dependent CYP17 mechanism of labor as in the sheep.
Speculatively, the rise in cortisol from placental CRF may have needed more time to act than in a more mature infant and the placental production of estrogen was simply too rapid a response. The function of the fetal adrenal may have been to delay the estrogen production compared to the placenta. The response of the fetal adrenal to ACTH is production of DHEAS but there is a damping inhibition of estrogen on that response. The problem with this theory is that in the primate, labor can occur without fetal adrenal function.
Stillborn infants still deliver from spontaneous labor. Infants with anencephaly do not develop a large fetal adrenal but still deliver spontaneously. At most, anencephalic infants have a pregnancy extended by 2 weeks, and this is as likely related to delayed ratio of oxygen use to placental function, as due to lower estrogen [4]. Adrenalectomy in fetal monkeys does not significantly prolong labor[5]. Fetal sulfatase deficiency which blocks the maternal elevation of estrogen production is not associated with prolonged gestation[6]. However there is other evidence that supports a role for the fetal adrenal in initiating labor.
The evidence for a role of the fetal adrenal in labor initiation in humans and monkeys starts with the observation that maternal serum estrogen and cortisol increase before and during labor. This does not prove causation, but requires an explanation. In monkeys, fetectomy prolongs labor which contradicts the study on adrenalectomy [7]. In humans, some intrauterine deaths do not lead to labor as evidenced by the existence of defibrination syndrome that is prevented by inducing labor that has become too delayed. Infants with sulfatase deficiency may require more Cesarean sections for failed labor. Thus, there may be a role for the fetal adrenal but it is not absolutely required to produce labor.
The most clear demonstration of a key role for fetal androgen as a precursor to estrogen in labor is that the direct intravenous infusion of androstenedione in monkeys produces early onset of normal labor compared to controls[8, 9]. (The authors cite a reference in a monograph that infusion of DHEAS does not increase maternal estrogen in monkeys, but no explanation is given.) Androstenedione like DHEA can be converted by aromatase in the placental syncytiotrophoblast to maternal estrogens. When these studies were repeated with an aromatase inhibitor to prevent conversion of the androgen to estrogen, as expected maternal estrogen did not increase, nor did premature labor ensue. However, when monkeys were infused with estradiol to produce a rise in estrogen comparable to that in labor, only myometrial contractions occurred but no cervical change and no preterm delivery. In none of the infusion experiments did progesterone decrease. The authors conclude that there must be paracrine effects at the local site of production[10]. An alternative hypothesis is that the conversions from androgens to estrogens regulate other processes that simply are not being measured in the experiments. The infusion experiments suggest that the fetal adrenal – estrogen pathway can initiate term labor.
In favor of the importance of the fetal adrenal is the investment of fetal resources to create such a large metabolically active organ. The CRF to ACTH to DHEAS to estrogen pathway plausibly can initiate labor, but the function of the fetal adrenal placental system is more complex than just the production of estrogen, as the androgen infusion experiments indicate. For example some DHEA goes to the fetal liver to produce estriol, not just to the placenta to produce maternal estrogen. As many others have observed, the existence of redundancy would be expected in so important a survival function as initiating labor. Fetal adrenal function may be a primary but not an exclusive initiator of term labor.
The progesterone receptor blocking drug RU 486 stimulates uterine contraction but not cervical change[11]. Infused estrogen can produce myometrial contractions, but does not dilate the cervix. Iatrogenic prostaglandins do dilate the cervix and initiate labor. CRF up-regulates membrane cyclooxygenase and this could be the link to successful labor using both estrogen and prostaglandin, as well as the mechanism to produce labor in the absence of fetal adrenal function.
If placental CRF is the main signal initiating term labor in humans as opposed to hypothalamic maturation, then what determines the timing of CRF secretion? If CRF can stimulate cyclooxygenase, where does this occur and how is it amplified? As noted in the chorioamnionitis discussion, it is possible that chorioamnionitis is a method for the uterus to amplify the cervical signal with increased inflammatory mediators induced by usually benign vaginal flora. These are important questions, particularly in relation to premature labor that need to be considered in future blogs.
Bottom line: The question of why do we have a fetal adrenal is ultimately a question of its fitness for survival, and I have speculated on how and why it may have come about. There is some evidence that its production of DHEA-S with conversion to estrogen in the placenta is stimulated by placental CRF as a stimulus for the initiation of labor.
1. Langlois, D., J.Y. Li, and J.M. Saez, Development and function of the human fetal adrenal cortex. J Pediatr Endocrinol Metab, 2002. 15 Suppl 5: p. 1311-22.
2. Liggins, G.C., et al., The mechanism of initiation of parturition in the ewe. Recent Prog Horm Res, 1973. 29: p. 111-59.
3. Giannoulias, D., et al., Localization of prostaglandin H synthase, prostaglandin dehydrogenase, corticotropin releasing hormone and glucocorticoid receptor in rhesus monkey fetal membranes with labor and in the presence of infection. Placenta, 2005. 26(4): p. 289-97.
4. Milic, A.B. and K. Adamsons, The relationship between anencephaly and prolonged pregnancy. J Obstet Gynaecol Br Commonw, 1969. 76(2): p. 102-11.
5. Mueller-Heubach, E., R.E. Myers, and K. Adamsons, Effects of adrenalectomy on pregnancy length in the rhesus monkey. Am J Obstet Gynecol, 1972. 112(2): p. 221-6.
6. Bedin, M., et al., Incidence of placental sulfatase deficiency on the mode of termination of pregnancy. Gynecol Obstet Invest, 1987. 24(2): p. 86-91.
7. Nathanielsz, P.W., J.P. Figueroa, and M.B. Honnebier, In the rhesus monkey placental retention after fetectomy at 121 to 130 days’ gestation outlasts the normal duration of pregnancy. Am J Obstet Gynecol, 1992. 166(5): p. 1529-35.
8. Mecenas, C.A., et al., Production of premature delivery in pregnant rhesus monkeys by androstenedione infusion. Nat Med, 1996. 2(4): p. 443-8.
9. Figueroa, J.P., et al., Effect of a 48-hour intravenous delta 4-androstenedione infusion on the pregnant rhesus monkey in the last third of gestation: changes in maternal plasma estradiol concentrations and myometrial contractility. Am J Obstet Gynecol, 1989. 161(2): p. 481-6.
10. Nathanielsz, P.W., et al., Local paracrine effects of estradiol are central to parturition in the rhesus monkey. Nat Med, 1998. 4(4): p. 456-9.
11. Haluska, G.J., et al., Temporal changes in uterine activity and prostaglandin response to RU486 in rhesus macaques in late gestation. Am J Obstet Gynecol, 1987. 157(6): p. 1487-95.
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