Endocrine System

Adrenal Gland, Cortex, X-Zone - Atrophy

Narrative
Comment:
The X-zone appears a few days after birth in mice of both sexes and is fully developed by weaning. The X-zone is located at the junction of the cortex and the medulla and is populated by cells with more eosinophilic cytoplasm than those of the zona fasciculata (Figure 1 and Figure 2). In male mice, the X-zone regresses at puberty (by about 5 weeks of age). In females, the X-zone persists for several weeks past puberty and then regresses more gradually in nulliparous females or more rapidly at first pregnancy. The extent of X-zone development and the rate of involution can also vary with mouse strain.

Normal regression (involution) of the X-zone in females of many mouse strains, including the B6C3F1 strain, progresses in morphologically distinct stages. The onset of regression begins with vacuolization of scattered constituent cells (Figure 1 and Figure 2). As regression continues, the number of vacuolated cells progressively increases until virtually all X-zone cells are affected. In later stages, the vacuolated X-zone cells undergo degeneration and necrosis, with subsequent overall X-zone architectural collapse, condensation, and eventual disappearance. A common end-stage sequela is the residual accumulation of pigment-laden cells in the perimedullary area formerly occupied by the X-zone. In males, X-zone regression is similar except that it usually occurs without vacuolization.

The function of the X-zone is unknown. Its normal development and regression are mediated by gonadal and thyroid hormones, so factors that alter levels of these hormones can affect the X-zone. For example, gonadectomy prolongs the persistence of the X-zone in female mice and prepubertal male mice and can cause the reappearance of the X-zone in postpubertal males. Administration of androgens like testosterone is followed by rapid disappearance of the X-zone in female mice. Administration of certain other chemicals can also affect the X-zone, resulting in asynchronous deviations, such as accelerated regression (Figure 3 and Figure 4) in treated groups compared with age-matched concurrent controls (Figure 1 and Figure 2).
Recommendations:
Adrenal cortical X-zone regression is a normal physiologic process, and its various stages are often incidental findings in mice of both sexes and at various ages. Features of normal X-zone regression stages (e.g., vacuolization, degeneration) and its end-stage sequelae (e.g., X-zone collapse, fibrosis, and pigment-cell accumulation) should not be mistaken for pathologic lesions. Thus, physiologic X-zone regression should not be diagnosed when it occurs in a similar, age- and sex-appropriate manner in both the control and treated mice in a given study. Abnormally accelerated (rapid) regression or, conversely, excessively lengthy persistence of the X-zone can be effects of treatment with various chemicals and exogenous hormones. However, in these cases, the X-zone morphology of treated animals will not be distinctive or exhibit pathognomonic pathologic features. Instead, the existence of a toxic effect manifests only as a disparity in the appearance (temporal stage) of the X-zone in treated animals compared with normal, age- and sex-appropriate concurrent study controls. For these reasons, X-zone toxicity in treated animals cannot be diagnosed in isolation but must be evaluated in the context of the physiologic temporal stage occurring in the study controls.
References:

Blystone CR, Elmore SA, Will KL, Malarkey DE, Foster PMD. 2011. Toxicity and carcinogenicity of androstenedione in F344/N rats and B6C3F1 mice. Food Chem Toxicol 49:2116-2124.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/21651954

Chhabra RS, Elwell MR, Chou B, Miller RA, Renne RA. 1990. Subchronic toxicity of tetrahydrofuran vapors in rats and mice. Fund Appl Toxicol 14:338-345.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/2318358

Dunn TB. 1970. Normal and pathologic anatomy of the adrenal gland of the mouse, including neoplasms. J Natl Cancer Inst 44:1323-1389.

Abstract: http://jnci.oxfordjournals.org/content/44/6/1323.abstract

Hershkovitz L, Beuschlein F, Klammer S, Krup M, Weinstein Y. 2007. Adrenal 20α-hydroxysteroid dehydrogenase in the mouse catabolizes progesterone and 11-deoxycorticosterone and is restricted to the X-zone. Endocrinology 148:967-988.

Full Text: https://doi.org/10.1210/en.2006-1100

Matsuura S, Suzuki K. 1986. Morphological changes in the submandibular glands and in the X zone of the adrenal gland following ovariectomy in mice. Cell Tissue Res 246:549-556.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/3791382

National Toxicology Program. 1993. NTP TR-443 Toxicology and Carcinogenesis Studies of Oxazepam (CAS No. 604-75-1) in Swiss-Webster and B6C3F1 Mice (Feed Studies). NTP, Research Triangle Park, NC.

Abstract: https://ntp.niehs.nih.gov/go/6030

National Toxicology Program. 1996. NTP TR-447. Toxicology and Carcinogenesis Studies of Acetonitrile (CAS No. 79-05-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). NTP, Research Triangle Park, NC.

Abstract: https://ntp.niehs.nih.gov/go/6038

National Toxicology Program. 2010. NTP TR-560. Toxicology and Carcinogenesis Studies of Androstenedione (CAS No. 63-05-8) in F344/N Rats and B6C3F1 Mice (Gavage Studies). NTP, Research Triangle Park, NC.

Abstract: https://ntp.niehs.nih.gov/go/33555

Nyska A, Maronpot RR. 1990. Adrenal gland. In: Pathology of the Mouse: Reference and Atlas (Maronpot RR, Boorman GA, Gaul BW, eds). Cache River Press, Vienna, IL, 509-536.

Abstract: http://www.cacheriverpress.com/books/pathmouse.htm

Rosol TJ, Yarrington JT, Latendresse J, Capen CC. 2001. Adrenal gland: Structure, function, and mechanisms of toxicity. Toxicol Pathol 29:41-48.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/11215683

Shire JGM, Beamer WG. 1984. Adrenal changes in genetically hypothyroid mice. J Endocrinol 102:277-280.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/6481284

Spencer PJ, Crissman JW, Stoot WT, Corley RA, Cieszlak FS, Schumann AM, Hardisty JF. 2002. Propylene glycol monomethyl ether (PGME): Inhalation toxicity and carcinogenicity in Fischer 344 rats and B6C3F1 mice. Toxicol Pathol 30:570-579.

Full Text: http://tpx.sagepub.com/content/30/5/570.full.pdf

Tanaka S, Matsuzawa A. 1995. Comparison of adrenocortical zonation in C57BL/6J and DDD mice. Exp Anim 44:285-291.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/8575542
  • Image of atrophy in the adrenal gland cortex x-zone from a female B6C3F1/N mouse in a subchronic study

    Adrenal gland, Cortex, X-zone - Normal in a female B6C3F1/N mouse from a subchronic study. Adrenal gland with moderate numbers of vacuolated cells in an age-matched control virgin female is shown for comparison with Figure 3. M = medulla, XZ = X-zone, ZF = zona fasciculata.

Enlarge Image
Enlarge All Images
<p>Adrenal gland, Cortex, X-zone - Normal in a female B6C3F1/N mouse from a subchronic study. Adrenal gland with moderate numbers of vacuolated cells in an age-matched control virgin female is shown for comparison with Figure 3. M = medulla, XZ = X-zone, ZF = zona fasciculata.</p>

Adrenal gland, Cortex, X-zone - Normal in a female B6C3F1/N mouse from a subchronic study. Adrenal gland with moderate numbers of vacuolated cells in an age-matched control virgin female is shown for comparison with Figure 3. M = medulla, XZ = X-zone, ZF = zona fasciculata.
<p>Adrenal gland, Cortex, X-zone - Normal in a female B6C3F1/N mouse from a subchronic study (higher magnification of Figure 1). Adrenal gland in an age-matched control virgin female is shown for comparison with Figure 4. M = medulla; XZ = X-zone.</p>

Adrenal gland, Cortex, X-zone - Normal in a female B6C3F1/N mouse from a subchronic study (higher magnification of Figure 1). Adrenal gland in an age-matched control virgin female is shown for comparison with Figure 4. M = medulla; XZ = X-zone.
<p>Adrenal gland, Cortex, X-zone - Atrophy in a virgin female B6C3F1/N mouse from a subchronic study. There is acceleration of X-zone (XZ) regression characterized by narrowing of the X-zone compared with Figure 1. M = medulla, ZF = zona fasciculata.</p>

Adrenal gland, Cortex, X-zone - Atrophy in a virgin female B6C3F1/N mouse from a subchronic study. There is acceleration of X-zone (XZ) regression characterized by narrowing of the X-zone compared with Figure 1. M = medulla, ZF = zona fasciculata.
<p>Adrenal gland, Cortex, X-zone - Atrophy in a virgin female B6C3F1/N mouse from a subchronic study (higher magnification of Figure 3). There is increased degeneration and necrosis of the X-zone (XZ) cells compared with Figure 2.</p>

Adrenal gland, Cortex, X-zone - Atrophy in a virgin female B6C3F1/N mouse from a subchronic study (higher magnification of Figure 3). There is increased degeneration and necrosis of the X-zone (XZ) cells compared with Figure 2.

Authors

Mark J. Hoenerhoff, DVM, PhD, DACVP
Associate Professor
Veterinary Pathologist, In Vivo Animal Core
Unit for Laboratory Animal Medicine
University of Michigan
Ann Arbor, MI

Georgette D. Hill, D.V.M., Ph.D.
Toxicologic Pathologist/Assistant Pathology Program Manager
Comparative Molecular Pathology Division
Integrated Laboratory Systems, Inc.
Research Triangle Park, NC

Margarita M. Gruebbel, DVM, PhD, DACVP
Senior Pathologist
Experimental Pathology Laboratories, Inc.
Research Triangle Park, NC

Reviewers

Thomas J. Rosol, DVM, PhD, DACVP
Professor of Veterinary Biosciences
Senior Advisor, Life Sciences, Technology Commercialization and Knowledge Transfer
The Ohio State University
Columbus, OH

Gordon Flake, MD
Staff Scientist
NTP Pathologist
Cellular and Molecular Pathology Branch
National Institute of Environmental Health Sciences
Research Triangle Park, NC