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Original Article

Anat Cell Biol 2024; 57(1): 61-69

Published online March 31, 2024


Copyright © Korean Association of ANATOMISTS.

Reversible effect of castration induced hypogonadism on the morphology of the left coronary arteries in adult male rabbits

Duncan Anangwe1 , Moses Madadi Obimbo1 , Ibsen Henric Ongidi1 , Peter Bundi Gichangi2

1Department of Human Anatomy and Medical Physiology, University of Nairobi, Nairobi, 2International Centre for Reproductive Health, Mombasa, Kenya

Correspondence to:Duncan Anangwe
Department of Human Anatomy and Medical Physiology, University of Nairobi, 14 Riverside Drive, Nairobi 30197-00100, Kenya
E-mail: anangweduncan83@gmail.com

Received: July 18, 2023; Revised: September 25, 2023; Accepted: September 26, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Hypogonadism is associated with an increased risk of coronary artery disease. This study sought to describe the histomorphology of the left coronary arteries of the adult male rabbit following orchiectomy and subsequent testosterone administration. We included 20 adult male rabbits, divided into a baseline group (n=2), an interventional group subjected to castration only (n=6), an intervention group subjected to castration followed by testosterone injection (n=6), and a control group (n=6). Key variables under investigation were serum testosterone levels, the intima-media thickness of coronary arteries, smooth muscle cell density, and adventitial collagen fiber density. The mean coronary arteries’ intimal medial thickness was significantly higher in the castrated group than in controls (0.488 mm and 0.388 mm, respectively), while the testosterone-injected group had a mean of 0.440 mm. Mean smooth muscle cell density was significantly lower in the castrated rabbits vs. controls (26.96% and 47.80%, respectively), this observation being reversed with testosterone injection (47.53%). Mean adventitial collagen fiber density was significantly higher in the castrated group than in controls (66.6% and 36.1%, respectively), with a marginal difference after testosterone injection (65.2%). This study demonstrates that castration-induced hypogonadism causes morphological changes in the coronary arteries that are partly reversible using testosterone injections. These findings provide a morphological basis for understanding the role of testosterone in coronary arteries.

Keywords: Testosterone, Hypogonadism, Coronary vessels, Cardiovascular diseases, Coronary artery disease

Male hypogonadism, characterized by low circulating testosterone levels, is one of the problems affecting males with advancing age [1, 2]. It is a relatively common endocrine disorder, the exact prevalence varying between populations. Age-related decline of serum testosterone levels in males can result from age-related illnesses or senescence-related decreases in secretion [3]. Androgens confer a protective influence on the cardiovascular system [4, 5].

Prospective clinical trials and meta-analyses indicate that circulating levels of endogenous androgens inversely correlate with risk factors and mortality from cardiovascular diseases [6-8]. Notably, chronically low testosterone levels are associated with a substantially higher risk of cardiovascular disease [9, 10], while patients with coronary artery disease or heart failure may elicit improved cardiovascular function after receiving testosterone treatment [11, 12].

Androgens benefit cardiovascular disease by directly acting on the cardiovascular system or modifying other risk factors. Experimental evidence suggests that physiologically high testosterone levels favourably influence the lipid profile, glycogen metabolism, hemostatic parameters, and vascular inflammation [13-16]. The immune-modulating effects of testosterone partly underpin its preventative influence on the development and progression of cardiovascular diseases like atherosclerosis [17, 18].

Most experimental studies have focused on changes in large-sized arteries induced by altering testosterone levels. Reported vascular structural changes under the setting of hypogonadism include increased carotid intima-media thickness (IMT) [19], increased collagen fiber density in the aorta [20], and decreased muscle density of carotid arteries [21]. Some evidence highlights that androgens have varying effects on different vascular beds [22]. Thus, the effect of testosterone on morphological alterations may not necessarily be a uniform pattern across all arteries. Further, little evidence indicates that structural vascular changes induced by varying testosterone levels are reversible.

Hypogonadism, characterized by diminished testosterone levels, has been linked to an elevated susceptibility to coronary artery disease. Given that coronary artery disease remains a significant cause of morbidity and mortality among middle-aged and older males [23], it is imperative to understand the role of testosterone and its deficiency in the structure of the coronary arteries. To elucidate the underlying mechanisms, our study delved into the alterations in histomorphology occurring within the left coronary arteries (LCAs) of adult male rabbits following orchiectomy and subsequent testosterone administration. Our primary aim was to ascertain the effects of castration-induced hypogonadism on coronary artery morphology and evaluate the potential reversibility of these changes through testosterone supplementation.

Study design

This study was a non-randomized quasi-experimental trial using the rabbit model. A total of 20 adult male rabbits aged 12 months were used in this study. We sought ethical approval to conduct the study from the Biosafety, Animal Use and Ethics Committee of the University of Nairobi in Kenya (Ethical approval number: FVMBAUEC/2019/98). Rules for the care and use of laboratory animals, as outlined by the Biosafety, Animal Use and Ethics Committee of the University of Nairobi, were followed. We adhered to the international guiding principles for biomedical research involving animals.

Animals and study setting

Rabbits of the white New Zealand species used as the study model are easy to handle, have low maintenance costs, and have a close cardio-physiological resemblance to humans. We obtained the animals from the Department of Veterinary Anatomy, University of Nairobi. All animals were selected at approximately 12 months because this is the age at which they attain sexual maturity. We excluded rabbits with visible pathology. The animals were housed in standard cages floored with wood shavings that were changed regularly. The animals were placed under a regular 12-hour light/dark diurnal cycle at a room temperature of 25°C±3°C and provided with standard rabbit pellets (Unga Farmcare) and water ad libitum.


We initiated the study by sacrificing two rabbits to establish baseline features of the LCAs. We then randomly divided the remaining 18 animals into interventional (12 rabbits) and control groups (6 rabbits). The interventional group underwent bilateral orchidectomy (surgical castration) under anaesthesia to induce hypogonadism, while the control group underwent sham surgery without actual orchidectomy. The surgeries were performed under sterile conditions using a combination of ketamine (30 mg/kg) and xylazine (2 mg/kg) intramuscularly for effective anaesthesia. Aspirin and amoxicillin were administered post-surgery for pain relief and infection prevention. Measurements of serum testosterone levels were taken in rabbits from all study groups. 5 ml of blood was collected from the jugular vein using heparinized bottles, and plasma samples were separated by centrifugation. A testosterone Enzyme Immuno-Assay kit (Immunometrics) was used to determine testosterone levels.

After the initial 6 weeks, six rabbits from the interventional group (castrated group) were euthanized, and their LCAs were harvested and processed for routine histology. This timeframe aligns with previous research indicating vascular morphological changes within 4 to 6 weeks in adult rabbits [24, 25]. After six weeks, the remaining six rabbits in the interventional group (testosterone-injected group) received weekly intramuscular injections of 25 mg of testosterone enanthate, a dosage used in past studies [26]. After 12 weeks, we sacrificed the remaining rabbits in both the interventional and control groups, harvested their LCAs, and processed the tissues for histological analysis. The sections of LCAs for histology were consistently obtained at the midpoint of the artery’s extent, equidistant from the aorta in all animals.

Tissue preparation and histological staining

The rabbits’ LCAs were fixed in 10% formalin for twelve hours. This process was followed by dehydration in increasing grades of alcohol (70% up to absolute alcohol) at one-hour intervals, then clearing in toluene. After that, the tissues were placed in an oven for wax infiltration. The LCAs were embedded in paraffin wax and oriented for transverse sectioning. After cooling, the embedded tissues were blocked using wooden blocks and then serially cut into 7-μm sections using a microtome. Fifteen 7-μm sections were randomly obtained from the ten ribbons, floated on a 60°C water bath, picked on a glass slide, and dried in an oven for 12 hours. Masson’s Trichrome staining displayed smooth muscle cells and adventitial collagen fibers, while hematoxylin and eosin (H&E) staining demonstrated the smooth muscle cell nuclei in the LCAs.

Microscopic analysis and morphometry

Photomicrographs of the sections were taken using a digital camera (Canon Powershot A640, 12 MP; Canon) mounted on a photomicroscope (Axiostar Plus Microimaging; Carl Zeiss). We noted and described the morphological changes of the LCAs. We conducted Stereological analysis using the Fiji Image J software (National Institute of Health), an open-source software for processing and analyzing images.

Statistical analysis

The variables we obtained included IMT, volumetric densities of adventitial collagen, and volumetric densities of smooth muscle. These measurements were obtained using standard morphometric methods in a past study on muscular arteries [21]. The collected data were then entered into the SPSS version 21 (IBM Co.) for coding, tabulation, and statistical analysis. Volumetric densities were expressed in frequencies. The data were grouped into the control group, castrated and testosterone-injected group. Mean differences in the parameters were determined as the differences from the controls. After confirming that the data were normally distributed using the Shapiro–Wilk test, analysis of variance (ANOVA) was used to compare means between groups. A P-value of ≤0.05 was considered significant at a 95% confidence interval. Data were visualized in tables, graphs, and photomicrographs.

Baseline findings and serum testosterone

From the baseline, the LCAs showed features of a muscular artery with three conventional tunics: tunica intima, tunica media, and tunica adventitia. The tunica intima comprised a solitary layer of endothelial cells positioned atop a delicate sub-endothelial connective tissue. The most prominent layer, tunica media, featured unbroken elastic lamellae intermingled with smooth muscle cells and collagen fibers. As for the tunica adventitia, it consisted of dense collagen fiber bundles encircling the vessel wall. Mean serum testosterone levels for the separate study groups were as follows: baseline had serum testosterone of 27.9 nmol/L, controls had 27.5 nmol/L, the castrated group had 0.9 nmol/L, and the testosterone-injected group had 15.4 nmol/L.

Morphometric parameters of the coronary arteries

From a visual analysis of the photomicrographs, the thickness of the intimal-medial layer of the LCAs appeared to be more prominent in the castrated group than in the controls (Fig. 1A, B). The thickness of the intimal-medial layer seemed smaller when the castrated rabbits were administered with testosterone, with a thickness comparable to the controls (Fig. 1A, C). A mean IMT of 0.388 mm was recorded in the control group, 0.488 mm in the castrated group, and 0.440 mm in the testosterone-injected group (Fig. 2A). The difference in IMT between all three experimental groups was statistically significant (P<0.05) (Table 1).

Table 1 . Differences in the mean intimal medial thickness of the control, castrated, and testosterone-injected groups using ANOVA

Study groupsMean difference (mm)P-value95% confidence interval
Castrated vs. control0.101*<0.0010.099–0.103
Castrated vs. testosterone injected0.048*<0.0010.046–0.051
Testosterone injected vs. control0.052*<0.0010.050–0.055

*Indicates statistically significant.

Figure 1. Representative slides of the left coronary artery wall from controls (A), castrated (B), and testosterone-injected rabbits (C). The double-ended arrow is IMT. Mean IMT was greater in the castrated group compared to the controls. Masson’s trichrome, ×100. TM, tunica media; TA, tunica adventitia; IMT, intima-media thickness.

Figure 2. Bar graphs showing means of the IMT (A), mean smooth muscle cell densities (B), and mean adventitial collagen fiber densities (C) of the left coronary artery in control, castrated, and testosterone-injected groups. IMT, intima-media thickness.

From a histological analysis, the density of smooth muscle cell nuclei appeared lower in the tunica media of LCAs of the castrated group compared to the controls (Fig. 3A, B). The density of smooth muscle cells was visually indistinguishable between the control and testosterone-injected groups in the photomicrographs (Fig. 3A, C). A mean of smooth muscle density of 47.80%, 26.96%, and 47.53% was determined in the tunica media of the LCA in control, castrated, and testosterone-injected groups, respectively (Fig. 2B). A significantly lower smooth muscle cell density was noted among the castrated group than controls and testosterone injected group (P<0.001). The smooth muscle cell density difference between controls and testosterone-injected animals was not statistically significant (P=0.495) (Table 2).

Table 2 . Differences in the mean smooth muscle cell densities of the control, castrated, and testosterone-injected groups using ANOVA

Study groupsMean difference (mm)P-value95% confidence interval
Castrated vs. control–20.84*<0.001–21.49 to –20.18
Castrated vs. testosterone injected–20.56*<0.001–21.18 to –19.95
Testosterone injected vs. control–0.270.495–0.78 to 0.23

*Indicates statistically significant.

Figure 3. Representative slides of the left coronary artery wall from the control group (A), castrated group (B), and testosterone-injected groups (C). There were fewer smooth muscle cells per unit area in the tunica media of the castrated group. Hematoxylin and eosin, ×100. TM, tunica media; TA, tunica adventitia.

From a visual impression of the histology of the slides, the tunica adventitia of the coronary LCAs appeared to be thicker in the castrated and testosterone-injected groups compared to the control (Fig. 1). The thickness of adventitial collagen in the castrated and testosterone-injected groups was not visually distinguishable (Fig. 1B, C). A mean adventitial collagen fiber density of 36.1% was recorded in the control group, 66.6% in the castrated group, and 65.2% in the testosterone-injected group (Fig. 2C). Compared to controls, a significantly higher fiber density was recorded among the castrated and the testosterone injected groups (P<0.001) (Table 3).

Table 3 . Differences in the mean adventitial collagen fiber densities of the control, castrated, and testosterone-injected groups using ANOVA

Study groupsMean difference (mm)P-value95% confidence interval
Castrated vs. control30.5*<0.00129.22–31.81
Castrated vs. testosterone injected1.40.0360.07–2.82
Testosterone injected vs. control29.1*<0.00128.04–30.10

*Indicates statistically significant.

A link between low serum testosterone levels and various cardiovascular risk factors and diseases has been described in previous studies [27]. Low testosterone level has been associated with atherosclerosis of most large arteries, while endogenous and exogenous androgens confer a protective effect [26, 28]. The coronary arteries, carotids, and aorta are known to be particularly vulnerable to atherosclerosis [24]. Some studies describe a link between low serum testosterone and morphological markers of atherosclerosis, such as IMT and luminal diameter in the aorta and carotid arteries [14, 29]. We were interested in the association of low testosterone levels with morphological markers of atherosclerosis, such as IMT, adventitial collagen fiber density, and smooth muscle density in the LCAs.

The typical serum testosterone levels in adult male rabbits vary seasonally and may range from 1.59–32.80 nmol/L [30, 31]. Our study’s serum testosterone levels were within range for the control rabbits and below the reference range for the castrated rabbits. The rabbits injected intramuscularly with testosterone regained testosterone levels within the reference range.

We found a larger IMT in the hypo-androgenic castrated rabbits than in controls. We also noted a significantly lower IMT in castrated rabbits that subsequently received testosterone injections. Cheruiyot et al. [21] similarly demonstrated increased IMT in common carotid arteries of hypogonadal rats. Few other studies indicate an inverse relationship between IMT and serum testosterone levels [17, 19], but an indication of whether testosterone administration would reverse the effects of hypogonadism on the vascular structure is barely reported.

Clinically, measuring IMT by ultrasonography is considered an early indicator of cardiovascular disease risk in individuals with hypogonadism. IMT is a reliable and sensitive marker of subclinical atherosclerosis and an independent predictor of cardiovascular events and target organ damage [32]. It is valuable in evaluating and stratifying cardiovascular disease risk, predicting long-term outcomes, and monitoring ongoing disease progression and regression [33]. The intimal thickness can be considered an adaptive mechanism to the blood flow, imparting lateral pressure and stress on the artery walls [34, 35].

The immunomodulatory effect of testosterone and its influence on programmed cell death in vascular smooth muscle cells may explain the association of increased IMT with hypo-androgenic states. Experimental studies indicate that testosterone suppresses pro-inflammatory cytokine activity and enhances anti-inflammatory factors [36]. Testosterone also regulates the apoptosis of vascular smooth muscle cells, which contributes to the progression of intimal hyperplasia and atherosclerosis [37].

Anecdotal evidence suggests that testosterone therapy would benefit hypoandrogenic males at risk of cardiovascular disease [12, 38]. However, routine use of testosterone in clinical settings of hypo-androgenic patients with cardiovascular disease has not been adopted due to the absence of larger, prospective, placebo-controlled studies. Our observation of reversing structural changes of the LCAs after testosterone administration in hypo-androgenic models supports the mounting evidence that testosterone therapy should be considered where appropriate.

We reported a reduction of smooth muscle cell density of the tunica media of the LCAs in castrated adult male rabbits. Similar findings have been noted in the smooth muscle of the common carotid artery [21] and the penis [39] under settings of induced hypogonadism. Smooth muscle density increased to control levels in adult male castrated rabbits subsequently injected with testosterone, suggesting a reversible effect.

A reduction in myofilament quantity is described in hypogonadal states [40]. Proposed mechanisms that may explain the decrease in smooth muscle in hypo-androgenic animals include programmed cell death, atrophy, and de-differentiation of smooth muscle cells into other phenotypes [41, 42]. Kang et al. [43] observed an upregulation of angiotensin II receptors within the vascular wall in hypo-androgenic states. Angiotensin II receptors are potential activators of caspases, the primary mediators of apoptosis. Their activation also causes the downregulation of antiapoptotic molecules such as B cell lymphoma 2 (BCL2) in smooth muscle cells [43].

Certain studies have touted an ‘androgen deficiency- associated atrophy’ of smooth muscle cells as seen in the penile corpus cavernosum [39, 44]. This atrophy is similar to skeletal muscle atrophy in males with low testosterone levels [45]. Experimental studies that performed blockade of 5α reductase also describe the de-differentiation of smooth muscle cells into other phenotypes, such as fibroblasts and adipocytes, which partially explain the reduction of smooth muscle density in hypogonadal states [41, 46].

An in vitro experiment further demonstrated that testosterone administration delayed the senescence of vascular smooth muscle while inhibiting collagen synthesis in ageing vascular tissue via growth arrest-specific protein 6/Axl-8 and Akt/FoxO1a-dependent pathways [47]. These mechanisms may explain the protective effect of testosterone against vascular pathology. Our observation of a smooth muscle cell density reversal with an injection of testosterone further supports the notion that testosterone could be therapeutic in managing cardiovascular diseases in hypogonadal states.

The present study demonstrates increased collagen fiber density in the tunica adventitia of the LCAs in hypo-androgenic rabbits. Other studies have reported similar changes in collagen fibers in the common carotid artery [21] and the penis [39] under induced androgen deficiency. We also found that vascular adventitial collagen fiber density remained elevated after administering testosterone to castrated rabbits. It is plausible that an increase in collagen deposition is a long-term phenomenon that is not easily reversible with the restoration of hormone levels.

Multiple mechanisms have been proposed to explain how androgens influence vascular collagen deposition, including regulating transforming growth factor β (TGF-β) production. Testosterone suppresses the expression of TGF-β; thus, in settings of low androgen levels, upregulation of TGF-β results in fibroblast activation and deposition of collagen fibers [48]. TGF-β also induces the differentiation of fibroblasts into the more synthetic myofibroblast phenotype. Hypo-androgenic states additionally upregulate angiotensin II receptors on smooth muscle, leading to myofibroblast differentiation and increased collagen deposition [43].

Previously, the tunica adventitia was assumed to play a passive role in the nutritional and physical integrity of the wall of an artery. Fresh evidence suggests that it plays an active role in the function, structure, and development of pathological processes in the arterial wall [49]. Traditional descriptions of tunica adventitia refer to it as almost entirely composed of macrophages and fibroblasts. Ogeng’o et al. [50] have additionally demonstrated immunoregulatory cells, progenitor cells, endothelial cells, and pericytes within the adventitia of carotid and coronary arteries.

The tunica adventitia is richly fibroelastic, with collagen fibers that confer tensile strength to withstand external forces and elastic fibers that enable stretching for vasodilation and constriction [51]. A disproportionate amount of collagen increases arterial wall stiffness and correlates with multiple vascular pathologies, including atherosclerosis and hypertension [49]. The collagen-elastin ratio is influenced by sex hormones, partly contributing to the gender disparity in cardiovascular illnesses. Fischer and Swain [52] demonstrated a correlation of low testosterone levels with a high collagen-elastin ratio in the aorta of male rats after castration. More recently, Jenkins et al. [20] showed increased collagen synthesis by adventitial fibroblasts in the coronary arteries of rats treated with testosterone. Further studies should clarify these disparate results and determine whether adventitial collagen changes in hypoandrogenism are amenable to testosterone therapy.

The partial reversal of adverse histologic changes with testosterone injection suggests that testosterone replacement therapy (TRT) might offer cardiovascular benefits [18, 30]. Clinicians managing hypogonadal patients, especially those at risk of or already diagnosed with coronary artery disease, may consider TRT as a potential therapeutic approach to mitigate the impact of hypogonadism on coronary artery morphology. However, the cautious administration of TRT and close cardiovascular monitoring would be imperative.

We acknowledge the limitations of our study. We could not account for any other morphological changes in the LCAs that may have been induced by the systemic reaction to tissue injury caused by surgical castration. We, therefore, also did sham surgeries on the scrotum in control animals to try and reproduce similar stress responses for a more precise comparison. We could not determine whether the decrease in smooth muscle composition resulted from atrophy, apoptosis, or both, and we recommend further immunohistology studies to assess the same.

In conclusion, we have shown that reduced testosterone levels are associated with the alteration of vascular structure in the LCAs in the castrated rabbit model. We have further demonstrated that some changes may be reversed with testosterone injection and serum testosterone level restoration. These findings may serve as a morphological basis to explain coronary artery disease associated with hypogonadism in males and the role of testosterone therapy in prevention. Further studies are required in human subjects to elucidate if testosterone administration may reduce the risk of coronary artery disease in hypogonadal males.

Conceptualization: DA. Data acquisition: DA. Data analysis or interpretation: IHO. Drafting of the manuscript: DA, IHO. Critical revision of the manuscript: MMO, PBG. Approval of the final version of the manuscript: all authors.

No potential conflict of interest relevant to this article was reported.

  1. Yeo S, Holl K, Peñaherrera N, Wissinger U, Anstee K, Wyn R. Burden of male hypogonadism and major comorbidities, and the clinical, economic, and humanistic benefits of testosterone therapy: a narrative review. Clinicoecon Outcomes Res 2021;13:31-8.
    Pubmed KoreaMed CrossRef
  2. Fraietta R, Zylberstejn DS, Esteves SC. Hypogonadotropic hypogonadism revisited. Clinics (Sao Paulo) 2013;68(Suppl 1):81-8.
    Pubmed CrossRef
  3. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86:724-31.
    Pubmed CrossRef
  4. Nettleship J, Jones R, Channer K, Jones T. Testosterone and coronary artery disease. Front Horm Res 2009;37:91-107.
    Pubmed CrossRef
  5. Cai JJ, Wen J, Jiang WH, Lin J, Hong Y, Zhu YS. Androgen actions on endothelium functions and cardiovascular diseases. J Geriatr Cardiol 2016;13:183-96.
  6. Smith MR. Androgen deprivation therapy for prostate cancer: new concepts and concerns. Curr Opin Endocrinol Diabetes Obes 2007;14:247-54.
    Pubmed KoreaMed CrossRef
  7. Kintzel PE, Chase SL, Schultz LM, O'Rourke TJ. Increased risk of metabolic syndrome, diabetes mellitus, and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer. Pharmacotherapy 2008;28:1511-22.
    Pubmed CrossRef
  8. Tivesten A, Vandenput L, Labrie F, Karlsson MK, Ljunggren O, Mellström D, Ohlsson C. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab 2009;94:2482-8.
    Pubmed CrossRef
  9. Saad F, Yassin A, Doros G, Haider A. Effects of long-term treatment with testosterone on weight and waist size in 411 hypogonadal men with obesity classes I-III: observational data from two registry studies. Int J Obes (Lond) 2016;40:162-70.
    Pubmed KoreaMed CrossRef
  10. Wu FC, von Eckardstein A. Androgens and coronary artery disease. Endocr Rev 2003;24:183-217.
    Pubmed CrossRef
  11. Rosano GM, Leonardo F, Pagnotta P, Pelliccia F, Panina G, Cerquetani E, della Monica PL, Bonfigli B, Volpe M, Chierchia SL. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 1999;99:1666-70. Erratum in: Circulation 2000;101:584.
    Pubmed CrossRef
  12. Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc 2015;90:224-51.
    Pubmed CrossRef
  13. Gyllenborg J, Rasmussen SL, Borch-Johnsen K, Heitmann BL, Skakkebaek NE, Juul A. Cardiovascular risk factors in men: the role of gonadal steroids and sex hormone-binding globulin. Metabolism 2001;50:882-8.
    Pubmed CrossRef
  14. Hak AE, Witteman JC, de Jong FH, Geerlings MI, Hofman A, Pols HA. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab 2002;87:3632-9.
    Pubmed CrossRef
  15. Ng MK, Liu PY, Williams AJ, Nakhla S, Ly LP, Handelsman DJ, Celermajer DS. Prospective study of effect of androgens on serum inflammatory markers in men. Arterioscler Thromb Vasc Biol 2002;22:1136-41.
    Pubmed CrossRef
  16. Svartberg J, von Mühlen D, Mathiesen E, Joakimsen O, Bønaa KH, Stensland-Bugge E. Low testosterone levels are associated with carotid atherosclerosis in men. J Intern Med 2006;259:576-82.
    Pubmed CrossRef
  17. Malkin CJ, Pugh PJ, Jones RD, Jones TH, Channer KS. Testosterone as a protective factor against atherosclerosis--immunomodulation and influence upon plaque development and stability. J Endocrinol 2003;178:373-80.
    Pubmed CrossRef
  18. Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab 2004;89:3313-8.
    Pubmed CrossRef
  19. Tsujimura A, Yamamoto R, Okuda H, Yamamoto K, Fukuhara S, Yoshioka I, Kiuchi H, Takao T, Miyagawa Y, Nishida M, Yamauchi-Takihara K, Moriyama T, Nonomura N. Low serum free testosterone level is associated with carotid intima-media thickness in middle-aged Japanese men. Endocr J 2012;59:809-15.
    Pubmed CrossRef
  20. Jenkins C, Milsted A, Doane K, Meszaros G, Toot J, Ely D. A cell culture model using rat coronary artery adventitial fibroblasts to measure collagen production. BMC Cardiovasc Disord 2007;7:13.
    Pubmed KoreaMed CrossRef
  21. Cheruiyot I, Olabu B, Kamau M, Ongeti K, Mandela P. Histomorphological changes in the common carotid artery of the male rat in induced hypogonadism. Anat Cell Biol 2018;51:284-91.
    Pubmed KoreaMed CrossRef
  22. Perusquía M, Espinoza J, Montaño LM, Stallone JN. Regional differences in the vasorelaxing effects of testosterone and its 5-reduced metabolites in the canine vasculature. Vascul Pharmacol 2012;56:176-82.
    Pubmed KoreaMed CrossRef
  23. Tardif JC. Coronary artery disease in 2010. Eur Heart J Suppl 2010;12(suppl_C):C2-10.
  24. Hayashi K, Saruta T, Goto Y, Ishii M. Impact of renal function on cardiovascular events in elderly hypertensive patients treated with efonidipine. Hypertens Res 2010;33:1211-20.
    Pubmed CrossRef
  25. Fan J, Kitajima S, Watanabe T, Xu J, Zhang J, Liu E, Chen YE. Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. Pharmacol Ther 2015;146:104-19.
    Pubmed KoreaMed CrossRef
  26. Alexandersen P, Haarbo J, Byrjalsen I, Lawaetz H, Christiansen C. Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits. Circ Res 1999;84:813-9.
    Pubmed CrossRef
  27. Maggio M, Basaria S. Welcoming low testosterone as a cardiovascular risk factor. Int J Impot Res 2009;21:261-4.
    Pubmed KoreaMed CrossRef
  28. Hanke H, Lenz C, Hess B, Spindler KD, Weidemann W. Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall. Circulation 2001;103:1382-5.
    Pubmed CrossRef
  29. Muller M, van den Beld AW, Bots ML, Grobbee DE, Lamberts SW, van der Schouw YT. Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation 2004;109:2074-9.
    Pubmed CrossRef
  30. Sanni AA, Arowolo ROA, Olayemi FO. Preliminary study on the effect of castration and testosterone replacement on testosterone level in the New Zealand male rabbit. Afr J Biotechnol 2012;11:10146-8.
  31. Moor BC, Younglai EV. Variations in peripheral levels of LH and testosterone in adult male rabbits. J Reprod Fertil 1975;42:259-66.
    Pubmed CrossRef
  32. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;115:459-67.
    Pubmed CrossRef
  33. Uthoff H, Staub D, Meyerhans A, Hochuli M, Bundi B, Schmid HP, Frauchiger B. Intima-media thickness and carotid resistive index: progression over 6 years and predictive value for cardiovascular events. Ultraschall Med 2008;29:604-10.
    Pubmed CrossRef
  34. Stary HC, Blankenhorn DH, Chandler AB, Glagov S, Insull W Jr, Richardson M, Rosenfeld ME, Schaffer SA, Schwartz CJ, Wagner WD. A definition of the intima of human arteries and of its atherosclerosis-prone regions. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb 1992;12:120-34.
    Pubmed CrossRef
  35. Deopujari R, Dixit A. The study of age related changes in coronary arteries and its relevance to the atherosclerosis. J Anat Soc India 2010;59:192-6.
  36. Yesilova Z, Ozata M, Kocar IH, Turan M, Pekel A, Sengul A, Ozdemír IC. The effects of gonadotropin treatment on the immunological features of male patients with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2000;85:66-70.
    Pubmed CrossRef
  37. Bennett NC, Gardiner RA, Hooper JD, Johnson DW, Gobe GC. Molecular cell biology of androgen receptor signalling. Int J Biochem Cell Biol 2010;42:813-27.
    Pubmed CrossRef
  38. Jockenhövel F. Testosterone therapy--what, when and to whom? Aging Male 2004;7:319-24.
    Pubmed CrossRef
  39. Olabu BO. Structural changes in the rabbit penile architecture in induced hypogonadism [PhD dissertation]. Nairobi: University of Nairobi; 2014.
  40. Traish AM, Goldstein I, Kim NN. Testosterone and erectile function: from basic research to a new clinical paradigm for managing men with androgen insufficiency and erectile dysfunction. Eur Urol 2007;52:54-70.
    Pubmed KoreaMed CrossRef
  41. Arnold JT, Isaacs JT. Mechanisms involved in the progression of androgen-independent prostate cancers: it is not only the cancer cell's fault. Endocr Relat Cancer 2002;9:61-73.
    Pubmed KoreaMed CrossRef
  42. Rzucidlo EM, Martin KA, Powell RJ. Regulation of vascular smooth muscle cell differentiation. J Vasc Surg 2007;45 Suppl A:A25-32.
    Pubmed CrossRef
  43. Kang NN, Fu L, Xu J, Han Y, Cao JX, Sun JF, Zheng M. Testosterone improves cardiac function and alters angiotensin II receptors in isoproterenol-induced heart failure. Arch Cardiovasc Dis 2012;105:68-76.
    Pubmed CrossRef
  44. Traish A, Kim N. The physiological role of androgens in penile erection: regulation of corpus cavernosum structure and function. J Sex Med 2005;2:759-70.
    Pubmed CrossRef
  45. Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract 2010;64:682-96.
    Pubmed KoreaMed CrossRef
  46. Corradi LS, Góes RM, Carvalho HF, Taboga SR. Inhibition of 5-alpha-reductase activity induces stromal remodeling and smooth muscle de-differentiation in adult gerbil ventral prostate. Differentiation 2004;72:198-208.
    Pubmed CrossRef
  47. Chen YQ, Zhao J, Jin CW, Li YH, Tang MX, Wang ZH, Zhang W, Zhang Y, Li L, Zhong M. Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway. Age (Dordr) 2016;38:60.
    Pubmed KoreaMed CrossRef
  48. Chipuk JE, Cornelius SC, Pultz NJ, Jorgensen JS, Bonham MJ, Kim SJ, Danielpour D. The androgen receptor represses transforming growth factor-beta signaling through interaction with Smad3. J Biol Chem 2002;277:1240-8.
    Pubmed CrossRef
  49. Stenmark KR, Yeager ME, El Kasmi KC, Nozik-Grayck E, Gerasimovskaya EV, Li M, Riddle SR, Frid MG. The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol 2013;75:23-47.
    Pubmed KoreaMed CrossRef
  50. Ogeng'o J, Ongeti K, Obimbo M, Olabu B, Mwachaka P. Features of atherosclerosis in the tunica adventitia of coronary and carotid arteries in a black kenyan population. Anat Res Int 2014;2014:456741.
    Pubmed KoreaMed CrossRef
  51. Ogeng'o J, Ominde BS, Ongeti K, Olabu B, Obimbo M, Mwachaka P. Reappraisal of the structure of arterial Tunica adventitia and its involvement in atherosclerosis. Anat J Afr 2017;6:824-33.
  52. Fischer GM, Swain ML. Effect of sex hormones on blood pressure and vascular connective tissue in castrated and noncastrated male rats. Am J Physiol 1977;232:H617-21.
    Pubmed CrossRef

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