|Year : 2021 | Volume
| Issue : 2 | Page : 79-83
A histological study on the developing adrenal gland in human fetuses
T Suresh Kumar1, S Sathish Kumar2, B Minu Rekha3
1 Associate Professor, Department of Anatomy, Government Vellore Medical College, Vellore, Tamil Nadu, India
2 Associate Professor, Department of Anatomy, Government Dharmapuri Medical College, Dharmapuri, Tamil Nadu, India
3 Assistant Professor, Department of Anatomy, Government Vellore Medical College, Vellore, Tamil Nadu, India
|Date of Submission||15-Sep-2020|
|Date of Decision||26-Sep-2020|
|Date of Acceptance||07-Jan-2021|
|Date of Web Publication||09-Apr-2021|
T Suresh Kumar
No: 70/5A, Vasantham Avenue, Vanapadi Road, Ranipet, Vellore - 636 108, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Adrenal gland has an outer cortex and inner medulla that vary structurally, functionally, and embryologically. The developing gland plays a major role in concordance development of various viscera of the fetus and in parturition. The fetal adrenal gland shows histological changes not only in the fetal cortex but also in capsule, permanent cortex, and medulla. The current study aims to look at the changes in the microstructure of the fetal adrenal glands at various gestational ages. Methodology: Forty adrenal specimens from dead fetuses of gestational age from 14 to 36 weeks were collected and processed for routine hematoxyline and eosin staining and studied under light microscope. The samples were grouped into I, II, and III based on their gestational age. The microscopic changes occurring in different gestational ages were studied and photographed. Results: The cortex become well defined by 18 weeks and increase in thickness till term. Blood vessels appear in the capsule as early as 15 weeks. The fetal cortex increases in thickness with increase in gestational age. Lymphocytic infiltrations were consistently noted in the permanent cortex. The neuroblastic nodules were noted in the medulla from 14 weeks and regressed with advancing gestational age. Conclusion: Increase in the size of the fetal adrenal gland is mainly due to the increase in the fetal cortex. The neuroblastic nodules were seen until 32 weeks of gestation. The lymphocytic infiltration in the fetal cortex opens a new avenue of research to study their role in mediating the cortical secretions in fetus.
Keywords: Chromaffin, fetal cortex, neuroblastic, nodule, suprarenal
|How to cite this article:|
Kumar T S, Kumar S S, Rekha B M. A histological study on the developing adrenal gland in human fetuses. Natl J Clin Anat 2021;10:79-83
|How to cite this URL:|
Kumar T S, Kumar S S, Rekha B M. A histological study on the developing adrenal gland in human fetuses. Natl J Clin Anat [serial online] 2021 [cited 2021 Jun 18];10:79-83. Available from: http://www.njca.info/text.asp?2021/10/2/79/313505
| Introduction|| |
Adrenal or suprarenal gland, a unique endocrine gland, is a crucial component of the hypothalamic–pituitary–suprarenal axis that is responsible for coordinating mammalian stress response and metabolism., In adults, the gland is completely covered by a distinct capsule, and the parenchyma is composed of an outer cortex and inner medulla. Microscopically and functionally, the cortex is divided into outer dark zona glomerulosa, middle pale zona fasciculata, and inner dark zona reticularis. Medulla is composed of anastomosing cords of chromaffin cells separated by abundant blood vessels.
The fetal adrenal cortex, in contrast, is composed of a dark stained superficial narrow zone beneath the capsule called the permanent cortex or definitive zone and a light stained deeper zone called the fetal cortex or zone. During the entire fetal life, the medulla is completely surrounded by the cortex. With the advancing gestational age, the fetal cortex becomes bulkier and constitutes about 5/6th of the entire cortex before term. At term and after birth, the fetal cortex undergoes senescence-induced apoptosis leaving behind only its outer most layer that differentiates into zona reticularis and the permanent cortex expands to give rise to the zona glomerulosa and fasciculata.,, Medulla is composed of large blood vessels, scattered around them are few large cells called the neuroblasts derived from the neural crest cells. The chromaffin cells show their presence by the 10th week of fetal life., The steroidogenesis of the fetal adrenal gland under the influence of corticotropin-releasing hormone secreted by the placenta is considered to be essential for the initiation of parturition. In addition, the secretions of fetal suprarenal cortex influence the maturation of the lungs, liver, and digestive tract.,
As the microstructure of fetal adrenal cortex undergoes enormous change during its development and growth playing a vital role in the normal parturition, it has been subjected to much investigations in the recent years. Changes are also seen in the capsule, permanent cortex, and medulla apart from fetal cortex. Hence, the current study aims to look at the changes in the microstructure of the fetal adrenal glands at various gestational ages.
| Methodology|| |
The study was carried in the Institute of Anatomy, Madras Medical College, Chennai, Tamil Nadu, after the approval of the Institutional Ethics Committee (IRB Approval No: 14597/ME5/Ethics Dean/MMC/2010). After obtaining informed consent, forty fetal adrenal gland specimens from spontaneously aborted fetuses of gestational age ranging from 14 weeks to 36 weeks were obtained from Institute of Obstetrics and Gynaecology, Chennai, Tamil Nadu. History of maternal sepsis, fetuses with gross congenital malformations, and with anomalies involving central nervous system and genitourinary tract were excluded from the study. The samples of the fetal adrenals were obtained by meticulous dissection and fixed with 10% formalin for 10 days. They were grouped into I, II, and III based on their gestational age. The samples were processed for routine hematoxylin and eosin stain and the slides were studied under Olympus Research Microscope, Model Cx2li and photographed using Magcam DC 5Mp Camera and Magvision software Version x36, 3.7.6820 (New Delhi, India) under ×4, ×10, ×40, and 100× resolution.
| Results|| |
The gestational age-wise description of the cytoarchitecture and microscopic structure of the fetal adrenal gland is as follows [Table 1].
|Table 1: Histological features of adrenal gland in the Groups I, II, and III|
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Group I (14–20 weeks) (n = 12)
The fetal adrenals showed an incomplete, and thin developing capsule by 14 weeks which became thick and well distinct by 18 weeks. The appearance of the blood vessels in the capsule occurred as early as 15 weeks of gestation. The demarcation between the cortex and medulla was ill defined. The cortex was composed of a superficial darker permanent cortex occupying the outer one-fourth of the cortical thickness and a lighter zone occupying the inner third-fourth of the cortex [Figure 1]. The permanent cortex was composed of oval-to-round small cells with heterochromatic nucleus. The cells were arranged in the form of clusters and ill-defined arcades by 14 and 16 weeks, respectively. The fetal cortex showed larger pale stained polygonal cells with euchromatic nucleus arranged in the form of parallel cords separated by blood vessels. Deeper layers showed small oval-to-round cells dark stained with heterochromatic nucleus arranged in the form of anastomosing cords [Figure 1]. The indistinct medulla showed very few blood vessels with numerous ganglionic cells. These cells were large irregular, highly eosinophilic with cytoplasmic processes. It had vesicular nucleus and prominent nucleolus [Figure 2]. Neuroblastic nodules were seen in groups distributed within the capsule, cortex, and medulla from 14 weeks onward and were more numerous. The neuroblastic cells were small oval-to-round cells with heterochromatic nucleus surrounded by a thin rim of cytoplasm [Figure 2].
|Figure 1: Section of human fetal adrenal gland of gestational age 16 weeks. C: Capsule, PC: Permanent cortex, FC: Fetal cortex, M: Medulla (H and E, ×10)|
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|Figure 2: Section shows human fetal adrenal gland of gestational age 15 weeks showing ganglionic cell (thick arrow) and neuroblastic nodule (thin arrow)|
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Group II (>20–28 weeks) (n = 14)
The capsule and trabeculae were well developed, thick with abundant collagen and fibroblast cells, and showed increased vascularity. The permanent cortex was thinner occupying the outer one-fifth of the cortex and cells arranged in well-defined semilunar arc with central core of clear area [Figure 3]. Lymphocytic infiltrations were consistently noted in subcapsular part of the permanent cortex [Figure 3]. The deeper fetal cortex was bulky, well defined, occupying the inner 4/5 of the cortex, and their cells were large, pale stained with euchromatic nucleus. Few cells appeared vacuolated [Figure 3]. Medulla was more distinct with large ganglionic cells with granular cytoplasm and few cytoplasmic processes. These cells were more in number when compared to the Group I. Neuroblastic nodules were seen as small cluster of basophilic neuroblastic cells without encapsulation. They were more numerous within the deeper cortex and medulla after 20 weeks attained maximum size by 24 weeks. The nodules within the medulla were also seen surrounding the sinusoids. The number of nodules was less compared to Group I. A central medullary vein is clearly identifiable by 24 weeks of gestation.
|Figure 3: Fetal adrenal gland of gestational age 24 weeks showing permanent cortex with cells arranged in arc pattern (thick arrow) (H and E, ×40). Lymphocytic infiltration in the superficial layers of adrenal cortex beneath the capsule (thin arrow). C: Capsule, PC: Permanent cortex, FC: Fetal cortex|
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Group III (>28–36 weeks) (n = 14)
The capsule appeared very thick with densely arranged collagen fibers and fibroblast cells. Increased vascularity of the capsule was noted. The permanent cortex appeared very thin occupying the outer 1/6 and the deeper fetal cortex occupying the inner 5/6 of the cortex [Figure 4]. The cells of the permanent cortex were arranged in a glomerular pattern separated by capillaries. The cells of the fetal cortex showed fascicular arrangement of large vacuolated cells arranged along the sides of the capillaries. The innermost layer of cortical tissue was identified by smaller dark stained cells with heterochromatic nucleus and arranged in reticular pattern. The medullary ganglionic cells were largest with numerous cytoplasmic processes and granules. The medulla showed abundant sinusoids and well-developed central vein [Figure 5]. By 32 weeks, the neuroblastic nodules were less in number and smaller in size and were located only in the medulla. They were not seen from 36 weeks.
|Figure 4: Section of human fetal adrenal gland of gestational age 40 weeks. Showing thinned out permanent cortex and thick fetal cortex. C: Capsule, PC: Permanent cortex, FC: Fetal cortex (H and E, ×10)|
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|Figure 5: Section shows human fetal adrenal medulla of gestational age 40 weeks showing well developed chromaffin cells in clusters (thin arrow) and large ganglionic cell (thick arrow)|
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| Discussion|| |
The suprarenal gland begins to develop during the 5th week of intrauterine life. The coelomic epithelium adjacent to the developing gonadal ridge proliferates and a subset of these cells delaminates and enters the underlying mesoderm. These delaminating cells differentiate into large acidophilic cells forming the fetal suprarenal cortical cells. A second wave of delaminating cells subsequently migrates, proliferates, and forms a thinner definitive cortex that almost completely surrounds the fetal cortex.
The capsule of the fetal adrenal gland is thin and ill-defined till 15 weeks, well identified by 20 weeks and becomes well developed by 20 weeks., It completely surrounds the gland and trabeculae were evident by 20–25 weeks. Blood vessels are seen in the capsule by 25 weeks. The thickness of the capsule was 59–124 μm at 11–15 weeks and around 312 μm beyond 25 weeks. The increase in the thickness and vascularity of the capsule with advancing gestational age seen in the present study is consistent with the previous studies, whereas the appearance of blood vessels in the capsule is seen as early as 15 weeks of gestational age in contrast with the previous studies.
During the fetal period, the morphology of the adrenal cortex remains relatively constant. It consists of an outer definitive or permanent cortex and an inner fetal cortex., The definitive cortex occupies 1/4 of the cortex at 11–15 weeks which increased to 4/5 of cortex beyond 25 weeks. According to Sangma et al. 2008, the permanent cortex occupies 1/4–3/4 of the cortex from 11 to 25 weeks. Both the studies suggest that the permanent cortex increases with gestational age. The present study, in contrast with the previous studies, shows a decrease in the thickness of the permanent cortex from 1/4 to 1/6 of the cortex by 14–28 weeks of gestation.
The cells of the definitive cortex were 6–7 layers by 11–15 weeks, 5–6 layers by 15–20 weeks, 2–4 layers 20–25 weeks, and 1–2 rows beyond 25 weeks. The cells were small structurally proliferative in nature and are lipid poor until mid-gestation. As gestation advances, the cells accumulate cytoplasmic lipid and start resembling steroidogenically active cells. The cells of permanent cortex were small oval to round with heterochromatic nucleus. The present study is consistent with the previous studies with respect to structure of the cells of the permanent cortex.
The cells of the permanent cortex were present in U-shaped arrangement/clusters during 11–15 weeks, semilunar arc, or groups 15–20 weeks and glomerular arrangement of cells from 20 weeks onward. In contrast, according to Sangma et al., 2008, the cells were uniformly scattered till 22 weeks and arranged in the form of arcs or acini from 26 to 32 weeks and in the form of glomerulus from 34 weeks onward. The present study shows form of clusters by 14 weeks and ill-defined arch-like arrangement by 16 weeks, semilunar arc-shaped arrangement by 28 weeks, and glomerular pattern separated by capillaries beyond 28 weeks in consistent with Khayathi et al., 2013.
The presence of T-lymphocytes in adult human adrenal zona reticularis and their direct cell–cell contact with the adrenocortical cells was reported immunohistochemically and under electron microscope, respectively. This interaction suggested a novel mechanism that may mediate adrenal androgen secretion, whereas lymphocytic infiltration of adrenal cortex in fetus has not been reported so far. In the present study, lymphocytic infiltrations were seen in superficial layers of permanent cortex. Such cortical infiltration of lymphocytes, their role, and mechanism of interaction with the superficial cortical cells in fetus are yet to be studied.
The fetal cortex, deeper strip of lighter zone, constitutes 3/4 of the cortex at 11–15 weeks decreased to 1/5 of the cortex at >25 weeks., In contrast, Boddeti et al., 2019, showed that the fetal cortex occupies 1/5 of cortex by 11 weeks to 4/5 of cortex by 25 weeks, suggesting that the fetal cortex increase in size with advancing gestational age. In the current study, the fetal cortex increases in thickness from 3/4 to 5/6 of the cortical thickness from 14 to 28 weeks which is consistent with Boddeti et al., 2019.
The fetal cortex is composed of large (20–50 mm) cells with ultrastructural characteristics typical of steroidogenic cells. In the outer regions, the cells are arranged in tightly packed cords. Whereas in the central portion, they form a reticular pattern separated by numerous sinusoids. Fasiculoreticular zone is 6–7 layered thick at 11–15 weeks and decreased to 1–2 cell layer thick with advancing gestational age. The cells were arranged in columns extending deeper into the cortex toward the medulla. Sinusoidal vessels increase with increase in gestational age., By the 30th week of gestation, the cortex manifests a rudimentary form of the adult adrenal cortex; the begin to resemble the zona glomerulosa and the zona fasciculata. In the present study, the fetal cortex shows larger polygonal cells pale stained with euchromatic nucleus till 20 weeks and later appeared to be vacuolated. The cells of its outer layer were arranged in the form of parallel cords separated by blood vessels, whereas deeper layers of the fetal cortex smaller oval-to-round cells dark stained with heterochromatic nucleus arranged in the form of anastomosing cords which were inconsistent with the previous studies.
Before being cordoned off by the formation of the suprarenal capsule, neural crest cells migrate into the suprarenal medullary region adjacent to the developing fetal cortex. These neural crest cells differentiate into chromaffin cells. The chromaffin cells are seen in medulla by 10 weeks. These neural crest cells are seen in the form of avascular clusters called neuroblastic nodules without any capsule. They were seen as a single large nodule by 7th week, splits into multiple small nodules by 12th week. These nodule are seen in maximum size and number between 17 and 20 weeks and regress thereafter.,, Khyathi et al., 2013, have reported that the nodules were not seen beyond 20 weeks. The present study is consistent with the previous studies with regard to the neuroblastic nodules and its cells, yet in contrast with Khyathi et al., 2013 that the nodules were seen up to 32 weeks of gestation. Although the medulla had neuroblastic nodules, till term, they were not considered to be the precursors of neuroblastic tumors but as part of normal morphogenesis of adrenal gland.
In addition to the chromaffin cells, few large ganglionic cells, with granular cytoplasm with vesicular nucleus with prominent nucleoli, were seen with in the medulla separated by sinusoids. These cells had numerous cytoplasmic processes and were seen scattered within the medulla. They were found to increase in number with gestational age. The present study is consistent with the previous study with respect to the ganglionic cells of the fetal adrenal medulla.
| Conclusion|| |
The increase in the size of the fetal adrenal gland with increase in gestational age is mainly due to the increase in the fetal cortex. The lymphocytic infiltration in the fetal cortex opens a new avenue of research to study their role in mediating the cortical secretions. The neuroblastic nodules were seen until 32 weeks of gestation which were considered as a part of normal development of adrenal medulla. These histological variations may help in the study of fetal adrenal physiology and endocrine pathology.
The authors would like to thank and pay respect to all those kind hearts who have donated their fetus for research and education purposes without whom this work would not have accomplished.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci 2006;8:383-95.
Stephens MA, Wand G. Stress and the HPA axis: Role of glucocorticoids in alcohol dependence. Alcohol Res 2012;34:468-83.
Mescher AL. Endocrine glands. In: JUNQUEIRA'S Basic Histology Text and Atlas. 12th
ed. Asia: McGrawHill Education; 2010. p. 354-8.
Schoenwolf GC. Larsen's Human Embryology. London: Churchill Livingstone/Elsevier; 2009. p. 716.
Khayati Sant Ram AS. Histogenesis of suprarenal gland in fetuses of different gestational age groups. Int J Biomed Res 2013;4:2675-82.
Sangma GT, lbochouba Y, Damayanti N. Development and maturation of suprarenal glands in human fetuses. J Anat Soc India 2008;2008:1-7.
Jaffe RB, Mesiano S, Smith R, Coulter CL, Spencer SJ, Chakravorty A. The regulation and role of fetal adrenal development in human pregnancy. Endocr Res 1998;24:919-26.
Johannisson E. The foetal adrenal cortex in the human. Its ultrastructure at different stages of development and in different functional states. Acta Endocrinol (Copenh) 1968;58:Suppl 130:7.
Boddeti RK, Devi VS. Histogenesis of suprarenal glands at different gestational age groups. Asian J Med Sci 2019;10:37-43.
Sangma GT, Ibochouba Y, Damayanti N. Development and Maturation of Suprarenal Glands in Human Fetuses. J Anat Soc India. 2008;57:1-7.
Ishimoto H, Jaffe RB. Development and function of the human fetal adrenal cortex: A key component in the feto-placental unit. Endocr Rev 2011;32:317-55.
Wolkersdörfer GW, Lohmann T, Marx C, Schröder S, Pfeiffer R, Stahl HD, et al
. Lymphocytes stimulate dehydroepiandrosterone production through direct cellular contact with adrenal zona reticularis cells: A novel mechanism of immune-endocrine interaction. J Clin Endocrinol Metab 1999;84:4220-7.
Ikeda Y, Lister J, Bouton JM, Buyukpamukcu M. Congenital neuroblastoma, neuroblastoma in situ, and the normal fetal development of the adrenal. J Pediatr Surg 1981;16:636-44.
Ram KS, Sharma M, Sharma A. Neuroblastic nodules and giant epithelial cells in suprarenal gland in fetuses of different gestational age groups. J Anat Soc India 2013;62:73-8.
Haldar A, Sahoo D, Banerjee P, Basu D, Chakraborty S. Histogenesis of suprarenal gland in aborted human fetuses of various weeks of gestation with implications in patients with neuroblastoma and other adrenal tumours after adrenalectomy. Endocrinology. 2019;8:1-4.
Turkel SB, Itabashi HH. The natural history of neuroblastic cells in the fetal adrenal gland. Am J Pathol 1974;76:225-44.
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