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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 12 4531-4535
Copyright © 1999 by The Endocrine Society

Original Studies

Effects of Postnatal Estradiol and Progesterone Replacement in Extremely Preterm Infants

Andreas Trotter, Ludwig Maier, Hans-Jörg Grill, Thomas Kohn, Matthias Heckmann and Frank Pohlandt

Section of Neonatology and Pediatric Critical Care Medicine, Children’s Hospital (T.K.), Clinical Pharmacy (L.M.), and the Department of Obstetrics and Gynecology (H.-J.G.), University of Ulm, 89075 Ulm, Germany

Address all correspondence and requests for reprints to: Dr. A. Trotter, Section of Neonatology and Pediatric Critical Care Medicine, Children’s Hospital, University of Ulm, Prittwitzstrasse 43, 89075 Ulm, Germany. E-mail: andreas.trotter{at}medizin.uni-ulm.de


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The fetus is supplied from the placenta with estradiol (E2) and progesterone (P) in increasing amounts during gestation. After delivery of a premature infant, placental supply is disrupted, resulting in a rapid decrease in E2 and P. Replacement of these placental hormones may restore intrauterine conditions and may be beneficial for bone mineral accretion, clinical course, and outcome. Thirty female infants with a median gestational age of 26.6 weeks (between 24.1–28.7) and a birth weight of 675 g (370–990) were randomized to receive E2 and P replacement, aiming to maintain plasma levels equaling the intrauterine levels, or no replacement. The E2 and P replacement was started iv and was followed by transepidermal administration for a total duration of 6 weeks. Repeated measurements included plasma levels of E2, P, FSH, and LH; uterine volume; calcium and phosphorus in spot urine specimens; and bone mineral accretion by single photon absorption densitometry. Further, the incidence of chronic lung disease and various clinical outcome data were recorded. The plasma levels of E2 and P were within the intrauterine range with median replacements of 2.30 mg/kg·day E2 (1.13–6.23) and 21.20 mg/kg·day P (11.23–27.36), iv. Three- and 6-fold higher doses of E2 and P were needed via the transepidermal route. The uterine volumes increased, and FSH and LH as indicators for biological effectiveness were significantly lowered with replacement. The bone mineral accretion rates tended to be higher, and the incidence of chronic lung disease tended to be lower (0% vs. 29%; P = 0.097). E2 and P replacement via iv and transepidermal routes is capable of maintaining plasma levels as high as those in utero with biological effectiveness. Trends toward improved postnatal bone mineral accretion and less chronic lung disease were found with the hormone replacement. Further and more extensive studies are warranted to address the role of this new approach in the care of extremely premature infants.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DURING PREGNANCY 17ß-estradiol (E2) and progesterone (P) plasma levels rise up to 100-fold in the mother (1). The determination of E2 and P in umbilical cord blood at different gestational ages has shown that the fetus is exposed to the same increasing levels. Within 1 day following delivery the levels of E2 and P drop by a factor of 100 in both the mother and the infant. Extremely low birth weight infants experience this deprivation much earlier than infants born at term. Nothing is known about the consequences of this deprivation of E2 and P at this early developmental stage.

It is generally accepted that estrogens and progestins have important impacts on bone metabolism (2, 3). However, to our knowledge there have been no studies published concerning the role of sex steroids in the postnatal bone mineralization of extremely low birth weight infants. Parallel to postmenopausal osteoporosis that is related to E2 deficiency (2), deprivation of the placental supply of E2 and P may contribute to the postnatal bone deficiency found in extremely low birth weight infants, known as the osteopenia of prematurity (4, 5).

Extremely low birth weight infants are prone to develop respiratory distress syndrome due to the deficient production of surfactant by alveolar type II cells (6). Respiratory insufficiency requires mechanical ventilation, and this may contribute to the development of chronic lung disease (7). The results of animal studies suggest that estrogens may play a role in fetal lung maturation and surfactant production (8). Therefore, a postnatal replacement of E2 and P may influence the incidence of chronic lung disease.

Placental function and fetal growth are well correlated, suggesting that the placenta plays a key role in the regulation of fetal growth (9). Interruption of intrauterine growth after extremely preterm birth can have long term negative effects on growth (10). E2 and P are major metabolic products of the placenta during mid- and late gestation. Would the replacement of these two hormones have an effect on postnatal growth in extremely low birth weight infants?

The aim of the present controlled randomized pilot study was to test the hypothesis that E2 and P replacement therapy improves postnatal bone mineral accretion. The clinical course and outcome data, e.g. incidence of chronic lung disease and postnatal growth, were also recorded.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Female infants with a gestational age of less than 29 weeks and a birth weight of less than 1000 g were eligible, as long as written informed consent was given by the parents. Only female infants were studied, because uterine growth was selected as the indicator for the biological effectiveness of the E2 and P replacement. Infants were randomized into two groups. One group received E2 and P replacement (replacement group), and the infants of the other group served as controls (control group). The study was approved by the institutional review board of the University of Ulm.

Methods

This pilot study was designed as a randomized trial without sample size calculation. E2, P, FSH, and LH plasma levels were measured in mixed umbilical cord blood and in blood samples drawn at 24 and 72 h on the fifth and seventh days, once a week until the seventh postnatal week, and during the ninth postnatal week. In the control group the weekly blood samples were restricted to the fourth and ninth weeks. Commercially available enzyme immunoassays (Enzymun-Test, Roche Molecular Biochemicals, Mannheim, Germany) were used. The method and accuracy of the E2 enzyme immunoassay have been described previously (11). E2 and P plasma levels were available from the laboratory within 4 h. Thereafter, the replacement therapy was adjusted to maintain plasma levels of 2000–6000 pg/mL E2 (7.34–22.03 nmol/L) and 300–600 ng/mL P (0.95–1.91 µmol/L), which correspond to the intrauterine levels (12, 13, 14, 15, 16, 17, 18).

The bone mineral content was measured within the first week of life and at the end of the replacement period using single photon absorption densitometry (model 278/C, Norland Corp., Fort Atkinson, WI). Three to five scans were performed at the midhumerus without repositioning. The coefficient of variation is approximately 3% (19). The bone mineral accretion (milligrams per cm/100 g) was calculated as the difference between the two bone mineral content measurements divided by the weight gain. The parenteral and enteral mineral supplementations were individually adjusted, as described previously in detail (20). The supplementation was classified as sufficient if calcium levels of 1.2 mmol/L or more and phosphorus levels of 0.4 mmol/L or more were excreted simultaneously in 50% or more of all individual spot urine specimens taken twice weekly during the first 6 weeks. This classification was used to build subgroups with sufficient and insufficient mineral supplementation.

Postnatal somatic growth was determined once a week. The changes in body weight and body length were reported as relative increases related to the values obtained the week before.

The anteroposterior (H) and horizontal (W) diameters of the cervix and uterine length (L) from the top of the fundus to the bottom of the cervix were measured by ultrasound within the first week of life and after 3, 6, and 9 weeks. The uterine volume was estimated as H x W x L x 0.5.

The need for mechanical ventilation, surfactant, oxygen, and dexamethasone therapy and the rate of chronic lung disease (defined as requirement for additional oxygen later than the 36th week of postmenstrual age) were recorded.

E2 and P replacement

17ß-E2 [estra-1,3,5(10)-triene-3,17ß-diol, Fa. Synopharm, Hamburg, Germany) and P (pregn-4-ene-3,20-dione, Synopharm) diluted in 98% ethanol were added to a phospholipid-stabilized soybean oil emulsion (Intralipid, Pharmacia & Upjohn, Inc., Erlangen, Germany) used for parenteral nutrition. Several solutions were produced containing 0.05 g/mL fat, between 2.2 ng/mL and 0.22 mg/mL E2, and between 0.4–1250 µg/mL P (E2-P-lipid-5% mixture). In the replacement group constant and continuous 24-h iv infusion of the E2-P-lipid-5% mixture (median, 19.2 mL/kg·day; 10.9–32 minimum and maximum) was started after birth as soon as venous access was obtained. The control group received 15 mL/kg·day of an E2- and P-free lipid-5% mixture. The E2 and P replacement was continued for 6 weeks. If venous access was no longer indicated, E2 and P were administered transepidermally by means of an ointment. Ointments were prepared on the basis of lanolin alcohol, cetearyl alcohol, petrolatum, and propylene glycol containing 4.5–46 mg/mL E2 and 114–284 mg/mL P. The E2 concentrations were thus much higher than those in commercially available gels for postmenopausal use (0.6 mg/mL). Ointment doses were measured with a 1-mL syringe, and one to three doses (median, 0.50 mL/kg·day; 0.14–1.0) were applied to the abdominal skin and to the back (lumbar region), wearing gloves.

Statistical analysis

The Mann-Whitney U test was used to compare the results of the study groups. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
During the enrollment period, 40 female infants with a gestational age of less than 29 weeks and a birth weight of less than 1000 g were treated at the study center. Of these, 10 infants were not included in the study because informed consent from the parents was not given or not possible within the first day. From the remaining 30 infants, 15 were enrolled in each group. The characteristics of the 2 groups are shown in Table 1Go. Twenty-five (83%) of the enrolled infants survived. In the replacement group 2 infants died on the first postnatal day from septic shock and severe respiratory distress syndrome, respectively. In the control group 1 infant died at the age of 3 days from untreatable arterial hypotension. The other 2 control group infants died at the ages of 71 and 282 days from unexplained hepatopathy and severe bronchopulmonary dysplasia, respectively.


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  		Table 1. Clinical characteristics of 30 infants randomized into the replacement group and a control group

 
The median duration of the iv replacement of E2 and P was 20 days 12–44(12–44, minimum and maximum). Plasma levels of E2 and P were within the target ranges of 2000–6000 pg/mL E2 and 300–600 ng/mL P with a median dose of 2.30 mg/kg·day E2 (1.13–6.23 mg/kg·day) and 21.20 mg/kg·day P (11.23–27.36 mg/kg·day). Median doses of 6.68 mg/kg·day E2 (2.77–11.55) and 132.8 mg/kg·day P (85.5–238) were used via the transepidermal route. From all E2 and P plasma levels measured at the defined time points, 66% and 47% exceeded the lower target limits for E2 and P during iv replacement, respectively. During transepidermal replacement, 45% and 27% of E2 and P plasma levels exceeded the lower target limit, respectively. Figure 1Go shows the E2 and P plasma levels of both groups at the different time points.



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  		Figure 1. Plasma levels of E2 and P in preterm infants with (•) and without ({circ}) replacement of E2 and P at different postnatal ages. Medians and 10th and 90th percentiles (conversion factors to Systeme International units: E2, 3.67; P, 3.18). The dotted lines indicate the desired plasma levels of E2 and P. The E2 and P replacement period is indicated by the horizontal bar on the top of the figure.

 
Uterine volumes of the replacement group increased significantly during the replacement period toward the level of volumes found in newborn infants born at term and decreased after the replacement was stopped (Fig. 2Go). The uterine volumes of the control group remained significantly lower than those of the replacement group. Plasma levels of FSH and LH in the replacement group remained on a significantly lower level for the entire replacement period and increased thereafter (Table 2Go). At 9 weeks both groups showed similar levels.



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  		Figure 2. Uterine volumes of the E2 and P replacement group (•) and the control group infants ({circ}) at 1, 3, 6, and 9 weeks of postnatal age. The values are expressed as medians with 10th and 90th percentiles. The absolute median values are added on the top. Significant differences in uterine volumes between the groups were found at 3, 6, and 9 weeks postnatally (*, P < 0.05, by Mann-Whitney U test). On the right, mean values of uterine volumes from term and 2- to 12-month-old infants reported by Bundscherer et al. (23 ) are added for comparison to the results of our preterm infants.

 

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  		Table 2. Plasma levels of FSH and LH in the replacement and control groups at different times

 
The infants were divided into the subgroups defined in Materials and Methods. The median bone mineral accretion rates (with minimum and maximum) in the four subgroups are listed in Table 3Go. The highest bone mineral accretion rates were found in the replacement group when mineral supplementation was sufficient.


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  		Table 3. Bone mineral accretion rates (milligrams per cm/100 g wt gain) of the replacement and control group infants

 
In the replacement group, 9 of 13 (69%) infants were intubated compared with 11 of 14 (79%) in the control group. There was no difference between the groups in the type of ventilation used (high frequency ventilation, conventional ventilation, or both) or in the use of prenatal betamethasone for respiratory distress syndrome prophylaxis (Table 1Go). Seven (77%) infants of the replacement group and 9 (81%) infants of the control group received bovine surfactant. Dexamethasone to facilitate weaning/extubation and to prevent chronic lung disease was given to 3 (23%) infants in the replacement group compared with 7 (50%) in the control group. No infant in the replacement group developed chronic lung disease, but 4 (29%) in the control group did (P = 0.097).

The median weekly percent increases in body weight and body length were 11.2% (minimum and maximum, -14 to 32) and 2.8% (-5.9 to 15) for the replacement group and 9.8% (-13 to 30) and 2.2% (-2.6 to 14) for the control group (P = 0.47 and 0.92), respectively. They remained below the median intrauterine increases of 12.3% and 3.8% for body weight and body length that were calculated from the 50th percentile of intrauterine growth curves (21). Survival, morbidity data, and age and weight at discharge home are shown in Table 4Go. No significant differences between the groups were found.


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  		Table 4. Morbidity and outcome of the replacement and the control group

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Currently there is no study available examining the subsequent effects of early withdrawal from the placental supply of E2 and P on extremely preterm infants. To our knowledge, this is the first investigation which has studied the effects of placental hormone replacement therapy with E2 and P. This study was designed as a pilot study with low set numbers of patients because there was no experience with an E2 and P replacement in extremely low birth weight infants to draw upon.

We were able to demonstrate that intrauterine plasma levels of E2 and P can be maintained by constant and continuous iv application of an E2-P-lipid 5% mixture started within the first postnatal hours. The transepidermal administration of E2 and P by means of an ointment resulted less frequently in the desired E2 and P plasma concentrations and needs further improvement. Basic considerations about doses, iv preparations, and target plasma levels of E2 and P have recently been described in detail (11).

During pregnancy, the uterus of the female fetus grows (22). After birth, uterine size decreases to its prepubertal size within the first year of life (23, 24) in accordance with the postnatal drop in plasma E2 levels. We found that during E2 and P replacement, uterine volumes of the extremely preterm infants increased as they did in utero. As expected FSH and LH plasma levels remained suppressed during the E2 and P replacement period. The well known postnatal increase in FSH and LH that was seen in the control group occurred in the replacement group after the replacement had been stopped. These results provide evidence for the biological effectiveness of the E2 and P replacement.

In vitro studies on cultured fetal mouse bones demonstrate a dose-dependent stimulatory effect of E2 on bone formation and mineralization (25). Fetuses showed increased skeletal calcification after the pregnant mice had received varying doses of the synthetic estrogen diethylstilbestrol. Moreover, estrogen treatment in this early phase of fetal bone tissue development resulted in higher calcium contents and mineral apposition rates in adulthood compared with those in controls. This finding suggests an estrogen-imprinting effect on bone cell programming in fetal life (26). Therefore, it is conceivable that early deprivation of E2 in extremely low birth weight infants may have long term impact on bone mineralization. Intrauterine bone mineral accretion approximates 4.5 mg/cm·100 g wt gain (19, 27). It has been shown that intrauterine bone mineral accretion can be achieved by individually adjusted mineral supplementation (20). However, even if vitamin D and mineral supplementations are adequate, postnatal bone mineral accretion rates can lag behind the intrauterine rate. In our study the highest bone mineral accretion rates were found in infants with hormone replacement. As a group, those infants achieved the highest mineral accretion rates who were provided with both hormones and sufficient quantities of minerals. Bone mineral accretion of the control group was not affected by sufficient mineral supplementation. These results support our speculation that osteopenia of prematurity is not only dependent on mineral supply but may also reflect E2 and P deficiency.

Administration of E2 to pregnant rabbits increased the phospholipid and phosphatidylcholine content and the phosphatidylcholine/sphingomyelin ratio of fetal rabbit lung lavage, suggesting increased fetal lung maturation and surfactant production (8). Increases in alveolarization, number of type II alveolar epithelial cells, and lamellar bodies in type II cells have been shown as evidence of morphological lung maturation (28, 29). Furthermore, messenger ribonucleic acid levels of surfactant protein A and B in fetal rabbit lung cells are enhanced by maternal E2 administration (30). A lower rate of respiratory distress syndrome was found after a single im injection of aqueous estrogens immediately after birth (31). In our study the needs for intubation and surfactant therapy were similar in the two groups. Nevertheless, no infant in the replacement group developed chronic lung disease compared with 29% in the control group who did. The reviewed literature and the results of the study emphasize a possibly important role of E2 and P for lung function and lung maturation. Because chronic lung disease is a major determinant of postnatal morbidity and mortality in extremely low birth weight infants, postnatal E2 and P replacement may be promising.

Placental GH in the maternal circulation is significantly reduced in cases of intrauterine growth retardation (32). The somatotropic effects of placental GH on fetal growth seem to be mediated through the induction of insulin-like growth factor I (33). In baboon pregnancy, E2 increases the maternal plasma levels of placental GH (34). Therefore, E2 and P do not appear to have a direct role in the regulation of growth, but may act in utero via the regulation of placental somatotropic agents. Preterm delivery means loss of the placenta as a possible mediator of the effects of E2 on growth. The finding that the median percent increases in body weight and body length of the replacement group were below the intrauterine increases is in accordance with these considerations.

Our study, with its small number of infants, has a pilot character. It demonstrates that it is feasible postnatally to maintain the high intrauterine plasma levels with significant biological effectiveness in infants born very prematurely. No negative side-effects attributable to the E2 and P replacement were observed. Infants with E2 and P replacement showed trends toward improved bone mineral accretion if mineral supplementation was sufficient and toward reduced incidence of chronic lung disease. These promising results warrant further studies to address the role of this new approach in the care of infants born extremely prematurely.

Received May 3, 1999.

Revised July 15, 1999.

Accepted July 26, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals