Development and Clinical Significance of the Human Fetal Adrenal Gland as a Key Component of the Feto-Placental System: A Systematic Review

Abstract

Background: The human fetal adrenal gland is a unique endocrine organ with distinct morphology and functional dynamics, which is significantly different from the postnatal adrenal. Its rapid growth and vital steroidogenic role during gestation have positioned it as a key regulator of fetal development and pregnancy maintenance. Objectives: To provide a comprehensive overview of the morphogenesis, function, regulatory mechanisms, and clinical implications of the human fetal adrenal gland, highlighting recent advances in understanding its development and its role in prenatal and postnatal health outcomes. Methods: A systematic review was conducted, including original research articles focused on human fetuses or validated animal models, examining the genetic, molecular, and hormonal mechanisms underlying adrenal development and function. Studies were excluded if they were editorials, case reports, focused on adult adrenal physiology, had small sample sizes, or were non-English publications. Study quality was evaluated using PRISMA guidelines. Results: The fetal adrenal gland develops from both mesodermal and ectodermal origins, forming three primary zones: fetal, transitional, and definitive. Each zone has distinct functions and developmental pathways. The fetal zone, which predominates, is responsible for producing dehydroepiandrosterone sulfate, DHEA-S, which is crucial for placental estrogen synthesis. The adrenal gland undergoes rapid growth and functional maturation, regulated by ACTH, placental CRH, IGF, and the renin–angiotensin system. Disruption of adrenal function is associated with conditions such as preterm birth, adrenal hypoplasia, congenital adrenal hyperplasia, and intrauterine growth restriction. Emerging evidence suggests that fetal adrenal hormones may influence long-term health through fetal programming mechanisms. Conclusions: The fetal adrenal gland plays a critical and multifaceted role in fetal and placental development. This gland influences placental development via steroid precursors (DHEA-S → estrogen synthesis), while also being regulated by placental factors such as the corticotropin-releasing hormone. Understanding its complex structure–function relationships and regulatory networks is essential for predicting and managing prenatal and postnatal pathologies. Future research should focus on elucidating molecular mechanisms, improving diagnostic tools, and exploring long-term outcomes of altered fetal adrenal function.

1. Introduction

Among the endocrine glands in the human fetus, the adrenal gland stands out as particularly interesting due to its distinct structure and function in fetal life compared to the postnatal and adult gland [1]. The unique architecture of the fetal adrenal cortex—characterized by an unusually large fetal zone and a well-defined definitive zone—undergoes significant remodeling after birth, drawing the interest of specialists aiming to understand the unique role and characteristics of this organ [2,3].

This review comes from the desire to summarize the recent knowledge regarding the fetal adrenal gland and to emphasize the vital role it has in the development of the fetus. The objective is to describe the stages of morphogenesis of the adrenal gland during fetal development and to discuss clinical relevance: in particular, conditions such as intrauterine growth restriction, preterm birth, and other prenatal specific pathologies.

This article is an outline of the recent knowledge of the function and development of the human fetal adrenals, starting from conception to the transition to postnatal organ, to provide a comprehensive overview of the morphogenesis, function, regulatory mechanisms, and clinical implications of the human fetal adrenal gland, highlighting recent advances in understanding its development and its role in prenatal and postnatal health outcomes. We also give a short overview on related disorders between fetal-adrenal–placental interactions.

2. Methods

A systematic search was made for articles published in the last ten years, across multiple databases including PubMed, Scopus, and the Cochrane Library, using a combination of the following keywords: fetal adrenal gland development, morphogenesis of adrenal gland, fetal adrenal endocrine system, steroidogenesis in fetal adrenal gland, disorders of adrenal gland, feto-adrenal-placental system.

The inclusion criteria were original research articles involving human fetuses or validated animal models, with a focus on genetic, epigenetic, molecular, or hormonal mechanisms relevant to adrenal gland development and its role in the feto-placental system. Exclusion criteria included case reports, commentaries, and editorials, studies limited to adult adrenal physiology, investigations with very small sample sizes (fewer than 10 participants), and publications in languages other than English. (

Table 1. Inclusion/Exclusion Criteria.

Criteria	Inclusion Criteria	Exclusion Criteria
	1. original research articles. 2. studies with human fetuses or validated animal models research describing genetic, epigenetic, molecular or hormonal mechanisms related to the adrenal gland system. 3. feto-placental system regarding adrenal function.	1. case reports, commentaries, or editorials. 2. studies describing only adult adrenal gland physiology. 3. studies with very small samples (less than 10 participants) 4. studies in other languages than English.

) (Figure 1).

Regarding study selection, all titles and abstracts were initially screened by an independent reviewer. Full-text reviews were then performed for selected studies to confirm eligibility. Discrepancies were resolved through consensus discussion.

After the extraction of the relevant studies, the following data were extracted: the design of the study, the methods of analysis, the most important findings related to adrenal morphogenesis, gene expression, functional maturation and clinical relevance in pathology.

The quality of the studies was assessed using PRISMA guidelines, with attention to the study design, sample size, and the robustness of the conclusions drawn. The systematic review was conducted in accordance with the recommendations of the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement (please see the PRISMA checklist in Supplementary File S1).

To ensure clarity, we also provide a list of the included articles after the selection process, which is stated directly below the flowchart. This approach allows readers to trace the selection from the initial pool to the final set of studies analyzed. The articles that remained after the selection process correspond to the following references in this review: [4,5,6,7,8,9,10,11,12].

Both human and validated animal models were included to provide a comprehensive understanding of fetal adrenal development. While human studies offer direct clinical relevance, animal models—particularly those closely mirroring human adrenal physiology—allow for mechanistic insights and experimental approaches that are not feasible in human research. This dual inclusion enhances the translational value of the review by bridging basic science with clinical observations.

3. Risk of Bias

To minimize the risk of bias, the systematic review was conducted in accordance with the guidelines, which provided a structured framework for study selection, data extraction, and quality assessment. This approach helped ensure methodological rigor and transparency. Nevertheless, some degree of bias may persist due to the exclusion of non-English publications and small-sample studies, which could limit the comprehensiveness of the review and introduce language or selection bias. Additionally, the inherent limitations of the included studies, such as publication bias or variability in study design, may also influence the overall findings. The risk of bias for the included studies was assessed using the Cochrane Risk of Bias Tool and is low to moderate.

This review was not registered in any database.

4. Results

The studies included in this review provide valuable insights into three key areas of fetal adrenal development: fetal adrenal gland morphogenesis, hormonal regulation, steroidogenesis, and clinical implications.

4.1. Fetal Adrenal Gland Development

Between 1920 and 1960, most of the anatomical studies describing the morphology of human fetal adrenal were reported, and since then, the descriptions have not changed significantly, but its function and peculiarities still continue to fascinate the medical world [3].

From the developmental point of view, the adrenal glands develop from the mesodermal layer of the embryo, specifically from the intermediate mesoderm. They arise around the fifth week of gestation, with significant hormonal production starting by the eighth week [13]. The fetal adrenal gland is largest during the first half of gestation, supporting critical functions for the developing fetus. This gland suffers morphological changes throughout gestation; the structure and proportions of the adrenal gland change significantly. The fetal zone dominates during fetal life but regresses after birth, transitioning to the definitive cortex that will function in the adult [4,13].

Embryology is distinct and complex regarding the formation of this gland. The adrenal glands originate from mesoderm: one of the three primary germ layers formed in embryonic development. It has a dual embryological origin and that leads to the development of two main parts: the adrenal cortex and the adrenal medulla. The adrenal cortex arises from the coelomic mesoderm of the urogenital ridge, and the medulla arises from neural crest tissue [13,14]. The adrenal medulla forms from neural crest cells, which are ectodermal; these cells migrate from the neural tube during early development [15]. By around the seventh week, these neural crest cells populate the developing adrenal gland, differentiating into chromaffin cells that produce catecholamines. During the fifth week of fetal development, mesothelial cells from the posterior abdominal wall proliferate and form the fetal or primitive cortex of the adrenal. In fetuses, the adrenal cortex is composed mainly of the fetal zone, which is responsible for producing hormones that are vital for fetal development [3,13].

The current knowledge of the structure and development of adrenal gland describes that the formation involves cell proliferation, differentiation, apoptosis, and cellular hyper-differentiation. From week seven to week eight, the developing fetal gland acquires two rudimentary, but distinct, zones: the inner part that consists of large eosinophilic cells, and the outer definitive zone, which comprises small, densely packed basophilic cells [5]. Ultrastructural studies that involved in situ hybridization revealed a third zone named the transition zone, with cells that have intermediate characteristics. At about the ninth week of gestation, the developing human fetal adrenal is completely defined, and during the fetal period, the morphology of the adrenal cortex remains relatively constant [1,5,16].

These Three Zones Are Different Both in Terms of Location and Their Function (Figure 2)

The fetal zone, the best developed area during the fetal period, is characterized by large, polyhedral cells that are actively engaged in steroidogenesis. The fetal zone is the largest and most prominent part of the adrenal cortex during fetal life. It is located beneath the outer layer of the adrenal cortex. This zone expresses proteins (P450scc and P450c17) that are required for dehydroepiandrosterone sulfate synthesis. The primary function of the fetal zone is the synthesis of androgens, especially dehydroepiandrosterone sulfate. This hormone is crucial for the following: overall growth and development, the development of the reproductive system and secondary sexual characteristics, and maybe the most crucial role in fetal period is placental estrogen synthesis. In this role, DHEA-S is converted into estrogens by the placenta, playing a key role in maintaining pregnancy [9]. The hormone that mostly regulates this area is the adrenocorticotropic hormone (ACTH) [5,16,17].

The transitional zone is situated between the fetal zone and the definitive cortex in the adrenal gland. It is part of the cortex, but it specifically represents the part transitioning from the fetal to the postnatal structure. The cells in this zone are characterized by their arrangement in columns or cords and have a role in hormone production [18]. Early in gestation, it is functionally identical to the fetal zone, but late in gestation (after 25–30 weeks) it expresses different proteins (3 beta HSD, P450scc, and P450c17), and it is the site of glucocorticoid synthesis [17].

The definitive zone, often described as the definitive cortex, plays a key role in the later stages of adrenal function, particularly as the fetus transitions to postnatal life. Now we know that after 22–24 weeks, it expresses 3 beta hydroxysteroid dehydrogenase and P450scc, and therefore is the likely site of mineralocorticoid synthesis. This part of the adrenal gland continues to develop and maturate mostly after birth, starting at the time of delivery and continuing as the child grows [5,15].

Figure 2. Fetal adrenal gland development (zonation).

Figure 2. Fetal adrenal gland development (zonation).

Soon after birth, the human fetal adrenal undergoes rapid involution due to the rapid disappearance of the fetal zone, with a decrease in androgen secretion. As a consequence, the total weight of the glands decreases by approximately 50% [6,17]. The atrophy of the fetal zone appears to occur by apoptosis [6].

The prenatal adrenal growth rate is impressive. The weight and structure of the developing human adrenal gland increases rapidly from eight to ten weeks post-conception [16]. Increases in adrenal weight are mostly during the first trimester, but they continue until term [1]. By 20 weeks gestation, the gland becomes as large as the fetal kidney, a further doubling in fetal adrenal weight occurs thereafter, and by term, the fetal adrenal weighs approximately 5 g [3,17]. The cell number of the fetal zone is not necessarily higher, but the size of it is much larger than that of the definitive zone [19].

How is it possible for a single gland to develop such an interesting zonation? The numerous studies on the development of the adrenal cortex have generated a lot of hypothetical theories, but the most accepted model of adrenal cortical cytogenesis is the cell migration one. In this model, each zone is derived from a common pool of progenitor cells, which then migrate and differentiate to populate the cortical zones with different functions [3,19,20].

4.2. Function and Factors That Influence Development of Human Fetal Adrenal Gland

Regarding its function, the fetal adrenal gland has a vital and complex role in maintaining the pregnancy and the development of the fetus, and last but not least, in its development in the postnatal period [21].

The primary function of the human fetal adrenal HFA is to provide steroids, DHEA and DHEAS as precursors for the placenta to use in estrogen production. The zones of the HFA are functionally separated in its steroidogenic production. Of course, apart from precursors for the placenta, the fetal adrenal gland produces a multitude of other essential chemicals in development, and their production is different depending on the gestational age and the needs of the fetus. In each period of pregnancy, the secretion of certain specific proteins is activated, leading to the release of specific hormones [7].

The principal precursor for synthesis of steroids in the HFA is cholesterol. The cell membranes present a high concentration of receptors for low-density lipoproteins (LDL). adrenocorticotropic hormone (ACTH) causes an increase in the number of LDL binding sites, and through that process expends the uptake of LDL cholesterol for steroidogenesis [22]. New research describes that fetal adrenals obtain cholesterol from two sources: the first is de novo synthesis from (carbon) C2 units, and the other one is from lipoproteins from fetal plasma. The de novo source can only account for 30% of daily needs for synthesis, so the concentration of lipoproteins in fetal plasma is the main precursor, and it is very important [4,22,23].

The Main Functions of the Hormones Released by the Fetal Adrenal (Figure 3)

The fetal adrenal glands primarily produce androgens, particularly DHEA-S, which plays a vital role in the development of the fetus and in the estrogen synthesis of the placenta [7,24]. Through the hormones that it secretes, the fetal adrenal gland determines the development of the reproductive organs and sexual differentiation, the overall growth and development of fetal tissues, and stress responses in cases of pathological pregnancy. Hormones produced by the adrenal glands are involved in the maturation of various systems, including the lungs, through promoting surfactant production, and, last but not the least, transition to extrauterine life by adapting to life after birth by shifting hormone production to support the newborn’s physiological needs [24,25].

Besides the important role of DHEA-S, another group of hormones are decisive in fetal development; the fetal adrenal gland produces increasing amounts of cortisol as pregnancy progresses, particularly in the third trimester, for maturing the fetal lungs, preparing the liver glycogen stores for gluconeogenesis, and being part of the maturation of the gastrointestinal and immune system [8,25].

Aldosterone produced by the definitive zone helps regulate the fetal electrolyte balance and blood pressure, but its role becomes more crucial after birth [8].

Figure 3. Functions of each adrenal zone.

Figure 3. Functions of each adrenal zone.

4.3. Growth and Regulation Factors

The growth and regulation of the fetal adrenal gland is made with the help of interactions between various hormones, growth factors, and signaling pathways.

The hormonal regulation is mostly performed by the ACTH (Adrenocorticotropic Hormone) that is secreted by the fetal pituitary gland early in fetal development. Particularly, it is responsible for the production of DHEA-S, cortisol, and the stimulation of the growth adrenal cortex. DHEA-S serves as a precursor for placental estrogen production [8]. Cortisol production is essential for critical developmental growth, for lung maturation, liver function, and surfactant production [26].

The Placental Corticotropin-Releasing Hormone (CRH) produced in the placenta determines ACTH release from the fetal pituitary, and later in pregnancy it directly promotes the maturation of the fetal adrenal glands in preparation changes and the transition to life after birth [27].

The fetal adrenal gland is sensitive to angiotensin II, which is involved in regulating the growth of the adrenal cortex. The renin–angiotensin system also interacts with ACTH secretion, modulating adrenal growth and function together [28].

Apart from these essential regulatory systems, there are other factors that subtly modulate the fetal adrenal function. One of these factors is an insulin-like growth factor that is particularly important for adrenal growth and differentiation during fetal life. It is involved in the proliferation of adrenal cells and in the transition between the fetal and definitive zones. Besides this, steroidogenic enzymes are responsible for converting cholesterol into steroid hormones like cortisol and DHEA-S [19,29]. Their expression is regulated by both ACTH and local growth factors. For such a complex gland, interconnected systems are needed to ensure both predecessors and the correct function of secretion and regulation [29].

Genetic and epigenetic factors regulate the development of the fetal adrenal gland; mutations in specific genes can lead to malfunction of the gland, with the most common pathology being congenital adrenal hyperplasia [30]. Response to intrauterine pathological conditions, such as maternal stress or malnutrition, can impact fetal adrenal growth and function through epigenetic factors that change the regulation of the gland.

Another important factor is the placenta that behaves as an essential regulator, through hormones such as estrogen, progesterone and CRH, and as a barrier for maternal chemicals that can influence adrenal function.

Interaction Between the Placenta and Adrenal Fetal Gland and Its Role in the Initialization of Labor (Figure 4)

The adrenal–placental interaction is a vital regulatory system that ensures proper fetal development and the maintenance of pregnancy [4,9].

The placenta is both a producer of hormones and a site for the conversion of fetal adrenal steroids into hormones that are essential for fetal development. Its main functions include the conversion of DHEA-S produced by the fetal adrenal gland into estrogens (estradiol and estrone) through a series of enzymatic processes. These estrogens are key factors in maintaining uterine blood flow, the maternal metabolism that supports fetal growth and they prepare and promote uterine contractility in labor [9,31].

The conversion of DHEA-S to estrogens in the placenta progressively increases during pregnancy, and the estrogen levels play a significant role in initiating labor. High estrogen levels stimulate the production of prostaglandins and oxytocin receptors in the uterus, promoting uterine contractions and cervical ripening, leading to labor [31].

Another important aspect is the cortisol production in the adrenal cortex, which stimulates the fetal lungs to produce a surfactant for postnatal lung function. Cortisol also induces the release of a placental CRH (corticotropin-releasing hormone), which is a key regulator of labor. The fetal adrenal gland responds to the placental CRH by increasing cortisol and DHEA-S output. Placental CRH levels rise sharply before labor, amplifying the fetal adrenal response and stimulating contractions.

Figure 4. Interaction between placenta and adrenal fetal gland and its role in the initialization of labor.

Figure 4. Interaction between placenta and adrenal fetal gland and its role in the initialization of labor.

The clinical evaluation of the fetal adrenal gland can be performed in two ways: by imaging, or functionally, by dosing hormones

The imaging evaluation of fetal adrenal gland is mostly performed by ultrasound; this is the primary modality for fetal gland description. The fetal adrenal glands are visible from 18 to 20 weeks of gestation and they appear hypoechoic, with a distinct cortex and medulla. In the assessment of this gland, there are some key sonographic markers: increased adrenal size in fetal stress conditions (intrauterine growth restriction, premature labor), small or absent adrenal glands in congenital adrenal hypoplasia, and enlargement in cases of congenital adrenal hyperplasia [32].

When ultrasound findings are inconclusive, we can use a fetal MRI, which allows for a better visualization of the adrenal structure because of the superior soft tissue contrast. It is used mostly to describe tumors of this gland.

Functional evaluation of the gland can be performed by dosing hormones. This can be performed via fetal blood sampling by cordocentesis from the umbilical vein. From this sampling, we can dose fetal cortisol levels that can be useful in assessing adrenal function and maturity. This can be achieved with dehydroepiandrosterone sulfate (DHEA-S), which indicates fetal adrenal androgen production, or 17-hydroxyprogesterone (17-OHP), which is elevated in congenital adrenal hyperplasia [10,33].

Another way to appreciate the adrenal gland function is by amniotic fluid analysis. A 17-OHP measurement in amniotic fluid is used for a prenatal diagnosis of congenital adrenal hyperplasia, or elevated levels of 17-hydroxyprogesterone suggest enzyme deficiencies (21-hydroxylase deficiency).

Sometimes, we can cause maternal serum screening to reflect the adrenal and placental function, because low estriol levels may indicate fetal adrenal dysfunction.

Unlike other estrogens, estriol synthesis relies on collaboration between the fetal adrenal gland, fetal liver, and placenta, making it a valuable marker of both fetal and placental function. The production of estriol occurs through a three-step process involving these organs. The fetal adrenal gland lacks 3β-hydroxysteroid dehydrogenase, preventing it from converting pregnenolone into progesterone. Instead, it produces large quantities of dehydroepiandrosterone sulfate (DHEA-S), which enters the fetal circulation and reaches the fetal liver. There, DHEA-S undergoes hydroxylation to form 16α-hydroxy-DHEA-S: a crucial step, unique to the fetus. The placenta then takes up this compound and, with the help of placental aromatase, converts it into estriol (E3). Estriol is subsequently released into the maternal circulation, where it can be measured in both maternal serum and urine. Because estriol synthesis integrates hormonal contributions from the fetus, liver, and placenta, maternal estriol levels serve as a dynamic indicator of fetal adrenal and placental function. Low estriol levels may suggest fetal adrenal hypoplasia, anencephaly, or placental insufficiency [33].

This study is important for several reasons, as it provides critical insights into the complex development and function of the human fetal adrenal gland: an endocrine organ that plays a pivotal role during gestation. Key reasons why this study is significant include the following.

The study advances our understanding of fetal adrenal gland development. It describes the formation of distinct adrenal zones—fetal, transitional, and definitive—which are crucial for steroidogenesis, particularly the production of DHEA-S. This hormone is essential for placental estrogen synthesis, which supports pregnancy maintenance and fetal growth.

By elucidating the developmental process of the fetal adrenal gland, this study helps to clarify its role in overall fetal development, offering new insights into how the fetal endocrine system operates and matures during gestation.

The research sheds light on the intricate regulatory mechanisms controlling fetal adrenal development, including factors like ACTH, placental CRH, insulin-like growth factor IGF, and the renin–angiotensin system. Understanding these regulatory pathways provides valuable information on how the body coordinates hormonal functions during pregnancy and fetal development. The relationship between the fetal adrenal gland and the placenta is best understood as a dynamic, bidirectional regulatory system. On one hand, the fetal adrenal gland supplies crucial precursors such as dehydroepiandrosterone sulfate (DHEA-S), which the placenta converts into estrogens to sustain pregnancy, regulate uterine blood flow, and promote parturition. On the other hand, the placenta exerts regulatory control over the fetal adrenal through the secretion of hormones, such as the corticotropin-releasing hormone (CRH), estrogens, and progesterone, which modulate adrenal growth and steroidogenesis. This reciprocal signaling ensures that fetal development, maternal adaptation, and the timing of labor remain tightly coordinated. Disruption of either arm of this feedback loop—whether due to impaired adrenal steroidogenesis or placental dysfunction—can contribute to adverse pregnancy outcomes including intrauterine growth restriction, preterm birth, and preeclampsia. Thus, the feto-placental unit should be regarded as an integrated endocrine network, rather than isolated structures acting independently.

These insights are particularly important for understanding how the adrenal gland responds to external factors, such as stress or malnutrition, which could influence both fetal health and pregnancy outcomes.

This study addresses a gap in the current literature by systematically reviewing the molecular and hormonal mechanisms underlying adrenal development. As adrenal health is often overlooked in prenatal care, this study provides a comprehensive analysis of its role and offers a more thorough understanding of adrenal morphogenesis.

4.4. Clinical Implications of Our Findings and Future Proposals

Due to the complexity of this gland and its multifactorial role in the development of the fetus, numerous studies are still underway that attest the possible pathologies derived from an altered function of the fetal adrenal gland. Alterations in fetal adrenal function can lead to several clinical conditions that affect both prenatal and postnatal health.

Over time, numerous pathologies that are possibly derived from the alteration of fetal adrenal function have been studied, but these are difficult to perform, due to the fact that the unborn fetus is a delicate subject in scientific research. By studying the hormones separately, we can extract some possible pathologies involved. We will summarize here in broad terms the most important and studied derived pathologies, leaving room for the subsequent research of the lesser-known pathologies.

4.5. Preterm Birth

Among the most common pathologies associated with an abnormal secretion given by the fetal adrenal gland is premature birth. The fetal adrenal gland produces increasing amounts of cortisol as pregnancy progresses, particularly in the third trimester, maturing the fetal lungs, preparing the liver glycogen stores for gluconeogenesis, and being part of the maturation of the gastrointestinal and immune systems. Lack of cortisol may result in altered function of this systems [31,34].

The secretion of DHEA-S that converts to estrogens in the placenta progressively increases during pregnancy, and the estrogen levels play a significant role in initiating labor. High estrogen levels stimulate the production of prostaglandins and oxytocin receptors in the uterus, promoting uterine contractions and cervical ripening, leading to labor [35].

Understanding the adrenal response to stress could help manage preterm labor and intrauterine growth restriction more effectively.

4.6. Adrenal Hypoplasia

Adrenal hypoplasia is defined as the underdevelopment or malformation of the fetal adrenal glands, which may result from genetic mutations or developmental defects during gestation. There are a lot of genes involved in the regulation and function of this gland; mutations in genes such as DAX1 and SF-1 can result in adrenal hypoplasia, translating into insufficiency and defective steroidogenesis [11,30].

In adrenal hypoplasia, the adrenal cortex fails to develop completely, and that reduces the gland’s ability to produce essential hormones. The clinical manifestations may vary a lot, but most often, infants with signs of adrenal insufficiency manifest feeding problems, vomiting, hypotension, and dehydration. The most important syndromes related to adrenal hypofunction with aldosterone insufficiency are hyponatremia, hyperkalemia, and dehydration [30].

Hormonal replacement therapies and targeted interventions for adrenal insufficiencies could be optimized based on better insights into fetal adrenal programming and its long-term effects.

4.7. Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia is a group of genetic disorders caused by enzyme deficiencies affecting steroid hormone synthesis [11]. The most common form is 21-hydroxylase deficiency, and in this condition the production of cortisol and aldosterone is impaired, leading to the accumulation of precursors that are then converted into androgens [36]. This deficiency leads to a vicious pathological circle, because the lack of cortisol induces high production of the adrenocorticotropic hormone (ACTH) by the pituitary gland that stimulates androgen production, accentuating hyperandrogenism. The clinical translation of this situation in females is virilization with ambiguous genitalia at birth [37].

4.8. Intrauterine Growth Restriction

Intrauterine growth restriction is a condition where fetal growth is restricted; it has a multitude of factors but is often secondary to placental insufficiency. Altered adrenal development may contribute to placental insufficiency through a decrease in the precursors necessary for the maintenance and development of the fetus [38]. Postnatally, IUGR is associated with increased risks of hypoglycemia, impaired thermoregulation, feeding difficulties, neurodevelopmental delay, and long-term predisposition to metabolic syndrome and cardiovascular disease.

It goes both ways, because impaired placental function can lead to abnormal fetal adrenal development and dysfunction. In response to a suboptimal intrauterine environment, such as hypoxia or malnutrition, the fetal hypothalamic–pituitary–adrenal axis may become overstimulated, leading to elevated fetal cortisol levels, which can suppress growth [38,39].

4.9. Long-Term Health

Lately, in the literature, a new and very interesting concept emerged, called fetal programming. This concept refers to how changes in the intrauterine environment, including hormone production, can have lasting effects on organ functioning, predisposing individuals to chronic diseases later in life [12]. The most studied are a group of cardiovascular diseases, and the theory states that elevated cortisol in utero can lead to abnormal vascular and metabolic development that can predispose individuals to cardiovascular disease in adulthood. An altered fetal adrenal role in steroidogenesis can affect glucose metabolism during fetal life and can imbalance glucose tolerance, leading to type 2 diabetes later in adult life. Another role of cortisol is in brain development, especially in maturating the central nervous system; altered levels of cortisol can lead to cognitive issues or neurodevelopmental delays [40].

Research suggests that early alterations in fetal adrenal function could contribute to fetal programming, influencing long-term outcomes such as metabolic syndrome, cardiovascular diseases, and psychological disorders. Understanding how early adrenal hormone levels influence organ development and stress responses could lead to preventive strategies for these diseases [40].

Given the connection between fetal adrenal hormones and placental health, identifying disruptions in this interaction could provide early markers for adverse pregnancy outcomes, such as pre-eclampsia or placental insufficiency, and inform interventions to reduce risks.

4.10. Personalized Medicine

Insights into the molecular mechanisms governing fetal adrenal development could open avenues for personalized medicine for newborns, allowing clinicians to tailor treatment approaches based on individual risk profiles, especially in the case of adrenal-related congenital disorders [40].

Understanding individual variations in adrenal function could lead to more precise dosing of corticosteroids in newborns and infants, improving neonatal outcomes while minimizing potential side effects from overtreatment.

4.11. Maternal Health

The health of the fetal adrenal gland can also influence maternal well-being. Hormonal changes in the maternal adrenal glands, driven by fetal signals, may affect maternal metabolism and immune responses. This connection could help to identify pregnant women who are at risk for complications like gestational diabetes or hypertension, and enable early management to ensure both maternal and fetal health [12].

5. Discussion

The systematic review describes the complexity of fetal adrenal development, underlining the interaction between genetic, hormonal, and environmental factors. Research shows that adrenal morphogenesis begins early in gestation, with complex functional maturation beginning in the third trimester, as cortisol production prepares the system for birth.

The vital role of this gland for the development, maturation, and function of the fetal body and placenta is unquestionable, with the complexity of the factors it produces being extremely high.

This review systematically synthesizes the current knowledge on the development and function of the fetal adrenal gland, with a focus on its critical contributions to fetal growth and homeostasis. Specifically, it aims to delineate the stages of adrenal morphogenesis during fetal life and to explore the clinical implications of adrenal function in pregnancy-related conditions, including intrauterine growth restriction (IUGR), preterm birth, and other prenatal disorders.

The human fetal adrenal glands undergo drastic physiological changes during gestation that are not encountered in any other human gland. Their steroid products are essential for fetal organ maturation and for the timing of parturition. The placenta and the maternal adrenal form a unique materno-fetal system. Advances in the study of patients with adrenal development disorders have helped to elucidate some of the factors involved in the activity and regulation involved in HFA development and function.

Strengths and Limitations

This review provides a different perspective by focusing on the fetal adrenal gland as part of the larger feto-placental system, integrating the key aspects of morphogenesis, hormonal regulation, and clinical implications. Unlike studies that focus on isolated genetic or hormonal mechanisms, this work offers a comprehensive synthesis of how these processes interact within the fetal development context.

The limitation of this research is that most of the advanced studies rely on animal models, and that may not fully explain human adrenal development. Additionally, gene expression and epigenetic mechanisms are well-studied, but there are limited longitudinal data following human fetuses from early gestation through to birth. Although animal models provide valuable mechanistic data on adrenal morphogenesis and regulation, interspecies differences in adrenal zonation, steroidogenic enzyme expression, and developmental timing limit direct extrapolation to humans. Therefore, findings from animal studies must be interpreted critically and be integrated with the limited human data available.

Further research is needed to explain molecular mechanisms regulating the transition from DHEA-S to estrogen production, the timing of cortisol secretion, and epigenetic regulation of adrenal development.

6. Conclusions

The development and function of the fetal adrenal gland is a complex process that involves coordination between genetic, hormonal, and environmental factors. Such a complex process is hard to understand, but lately, the advances in biomolecular techniques have made the understanding much clearer. This effort is crucial for understanding the proper development of the fetus and for addressing pathological conditions. In future research, it is important to focus on the long-term impact of hormonal imbalance in fetal life [10].

In conclusion, the placental–adrenal system plays a pivotal role in fetal growth and maturation, with the fetal adrenal gland providing essential hormonal precursors for placental function. Any imbalance in this system can compromise fetal development and contribute to long-term adverse outcomes [12].

The latest studies hope to establish an exact link between the structural changes in the gland and the evolution of the pregnancy. At this moment, several researchers have revealed the possible correlations between the size of the intrauterine gland and the prediction of the moment of birth, with this being an extremely useful predictor in premature births or in the evaluation of fetuses with intrauterine growth restriction [2]. New studies must be developed to make the evaluation of this gland and intrauterine fetal status a real prenatal indicator.