Medical Physiology, 3rd Edition

The Maternal-Placental-Fetal Unit

During pregnancy, progesterone and estrogens rise to levels that are substantially higher than their peaks in a normal cycle

Following ovulation during a normal or nonconception cycle, the cells of the ovarian follicle functionally transform into luteal cells, which produce mainly progesterone but also estrogens (see pp. 1116–1117). However, the corpus luteum has a life span of only ~12 days before it begins its demise in the face of declining LH levels. As a consequence of luteal demise, levels of both progesterone and estrogens decline.

In contrast, during pregnancy, maternal levels of progesterone and estrogens (estradiol, estrone, estriol) all increase, reaching levels substantially higher than those achieved during a normal menstrual cycle (Fig. 56-7). These elevated levels are necessary for maintaining pregnancy. For example, progesteronethe progestational hormonereduces uterine motility and inhibits propagation of contractions. How are these elevated levels of female steroids achieved? Early in the first trimester, hCG that is manufactured by the syncytiotrophoblast rescues the corpus luteum, which is the major source of progesterone and estrogens. This function of the corpus luteum in the ovary continues well into early pregnancy. However, by itself, the corpus luteum is not adequate to generate the very high steroid levels that are characteristic of late pregnancy. The developing placenta itself augments its production of progesterone and estrogens, so by 8 weeks of gestation the placenta has become the major source of these steroids—the luteal-placental shift. Removal of the ovaries (with the corpus luteum) before the luteal-placental shift leads to miscarriage, whereas pregnancy continues normally if the ovaries are removed after the luteal-placental shift. The placenta continues to produce large quantities of estrogens, progestins, and other hormones throughout gestation.


FIGURE 56-7 Maternal levels of progesterone and estrogens just before and during pregnancy. The y-axis scale is logarithmic. The zero point on the x-axis is the time of fertilization. The progesterone spikes near –8 and –4 weeks refer to the two menstrual cycles before the one that resulted in the pregnancy. Estriol, produced from fetal adrenal androgens, increases only after 8 to 10 weeks, when fetal adrenal androgen production increases exponentially. (Data from Wilson JD, Foster DW, Kronenberg M, Larsen PR: Williams Textbook of Endocrinology, 9th ed. Philadelphia, WB Saunders, 1998.)

Estriol, which is not important in nonpregnant women, is a major estrogen—based on circulating levels—during pregnancy (see Fig. 56-7). imageN56-1


Role of the Fetal Hypothalamic-Pituitary-Adrenal Axis in Estriol Synthesis

Contributed by Sam Mesiano

Because 16α-hydroxylase is expressed only by the fetal liver, the level of estriol in the maternal circulation during pregnancy reflects the activity of the fetal hypothalamic-pituitary-adrenal axis. See Figure 56-9 for the enzymatic pathways in fetus and placenta. See Table 50-2 for a listing of the required P-450 enzymes.

After 8 weeks of gestation, the maternal-placental-fetal unit maintains high levels of progesterone and estrogens

Although it emerges as the major source of progesterone and estrogens (Table 56-5), the human placenta cannot synthesize these hormones by itself; it requires the assistance of both mother and fetus. This joint effort in steroid biosynthesis has led to the concept of the maternal-placental-fetal unit. Figure 56-8—which resembles the maps describing the synthesis of glucocorticoids, mineralocorticoids (see Fig. 50-2), male steroids (see Fig. 54-6), and female steroids (see Fig. 55-8)—illustrates the pathways that the maternal-placental-fetal unit uses to synthesize progesterone and the estrogens. Figure 56-9 summarizes the exchange of synthetic intermediates among the three members of the maternal-placental-fetal unit.

TABLE 56-5

Roles of the Mother, Placenta, and Fetus in Steroid Biosynthesis







LDL cholesterol

Adequate synthetic capacity for progesterone and estrogens



3β-Hydroxysteroid dehydrogenase
Aromatase (P-450arom)

Adequate cholesterol-synthesizing capacity
17α-Hydroxylase (P-450c17; needed to synthesize estrone and estradiol)
17,20-Desmolase (P-450c17; needed to synthesize estrone and estradiol)
16α-Hydroxylase (needed to synthesize estriol)



17α-Hydroxylase (P-450c17; needed to synthesize estrone and estradiol) in adrenal cortex
17,20-Desmolase (P-450c17; needed to synthesize estrone and estradiol) in adrenal cortex
16α-Hydroxylase (needed to synthesize estriol) in liver

3β-Hydroxysteroid dehydrogenase
Aromatase (P-450arom)


FIGURE 56-8 Synthesis of progesterone and the estrogens by the maternal-placental-fetal unit. Individual enzymes are shown in horizontal and vertical boxes. See Figures 50-254-6, and 55-8 for cellular localizations of enzymes. Chemical groups modified by each enzyme are highlighted in the reaction product. The fetus lacks 3β-hydroxysteroid dehydrogenase and aromatase (P-450arom), shown with blue background. The placenta lacks 17α-hydroxylase and 17,20-desmolase activity (contributed by the same protein, P-450c17) and 16α-hydroxylase (expressed only by the fetal liver); all three are shown with a brown background. Blue and brown color coding of enzymes distinguishes fetus from placenta, whereas color coding in previous steroidogenesis figures indicated subcellular localization.


FIGURE 56-9 Interactions of the maternal-placental-fetal unit. The details of the enzymatic reactions are provided in Figure 56-8. imageN56-1; HSD, hydroxysteroid dehydrogenase; SCCE, the side-chain-cleavage enzyme.

Unlike the corpus luteum, which manufactures progesterone, estrone, and estradiol early in pregnancy (see p. 1116), the placenta is an imperfect endocrine organ. First, the placenta cannot manufacture adequate cholesterol, the precursor for steroid synthesis. Second, the placenta lacks two crucial enzymes that are needed for synthesizing estrone and estradiol. Third, the placenta lacks a third enzyme that is needed to synthesize estriol. The enzymes missing from the placenta are listed in Table 56-5, and they also are indicated with a brown background in Figures 56-8 and 56-9.

The maternal-placental-fetal unit overcomes these placental shortcomings in two ways. First, the mother supplies most of the cholesterol as LDL particles (see p. 968). With this supply of maternal cholesterol, the placenta can generate large amounts of progesterone and export it to the mother, which solves the problem of maintaining maternal progesterone levels after the corpus luteum becomes inadequate. Second, the fetal adrenal gland and liver supply the three enzymes that the placenta lacks. The fetal adrenal glands are up to this metabolic task; at term, these glands are as large as those of an adult.

The fetus does not synthesize estrogens without assistance, for two reasons. First, it cannot, because the fetus lacks the enzymes that catalyze the last two steps in the production of estrone, the precursor of estradiol. These two enzymes are also necessary to synthesize estriol. The enzymes missing from the fetus are listed in Table 56-5, and they also are indicated with a blue background in Figures 56-8 and 56-9. Second, the fetus should not synthesize estrogens without assistance. If the fetus were to carry out the complete classic biosynthesis of progesterone and the estrogens, it would expose itself to dangerously high levels of hormones that are needed not by the fetus but by the mother.

The fetus and its placenta use three strategies to extricate themselves from this conundrum. First, because the fetus lacks the two enzymes noted above, it never makes anything beyond dehydroepiandrosterone (DHEA) and 16α-hydroxy-DHEA (see Fig. 56-8). In particular, the fetus cannot make progesterone or any of the three key estrogens. Second, the placenta is a massive sink for the weak androgens that the fetus does synthesize, which prevents the masculinization of female fetuses. Third, the fetus conjugates the necessary steroid intermediates to sulfate, which greatly reduces their biological activity (see Fig. 56-9). Thus, as pregnenolone moves from the placenta to the fetus, it is sulfated. The products of fetal pregnenolone metabolism are also sulfated (DHEAS and 16α-hydroxy-DHEAS) as long as they reside inside the fetus. It is only when DHEAS and 16α-hydroxy-DHEAS finally move to the placenta that a sulfatase removes the sulfate groups, and thus the placenta can complete the process of steroidogenesis and can export the hormones to the mother.





Upper motor neuron



Significantly impaired

Lower motor neuron



Less impaired