High altitude exposure affects male reproductive parameters: could it also affect the prostate?

Abstract

Living at high altitudes and living with prostatic illness are two different conditions closely related to a hypoxic environment. People at high altitudes exposed to acute, chronic or intermittent hypobaric hypoxia turn on several mechanisms at the system, cellular, and molecular level to cope with oxygen atmosphere scarcity maintaining the oxygen homeostasis. This exposure affects the whole organism and function of many systems, such as cardiovascular, respiratory, and reproductive. On the other hand, malignant prostate is related to the scarcity of oxygen in the tissue microenvironment due to its low availability and high consumption due to the swift cell proliferation rates. Based on the literature, this similarity in the oxygen scarcity suggests that hypobaric hypoxia, and other common factors between these two conditions, could be involved in the aggravation of the pathological prostatic status. However, there is still a lack of evidence in the association of this disease in males at high altitudes. This review aims to examine the possible mechanisms that hypobaric hypoxia might negatively add to the pathological prostate function in males who live and work at high altitudes. More profound investigations of hypobaric hypoxia’s direct action on the prostate could help understand this exposure’s effect and prevent worse prostate illness impact in males at high altitudes.

Learning whether hypobaric hypoxia might aggravate prostate disease is necessary to prevent the significant impact of this disease on the quality of life of men exposed to altitude and contribute to the approach to prevention of this pathology.

Graphical abstract

Introduction

A significant number of people around the world live and work in a hypobaric hypoxic environment [1–3]. High altitude (HA) exposure, define as an altitude equal or higher than 2500 m, in which the partial pressure of oxygen (PO₂) is reduced by a decrease in the atmospheric pressure (hypobaric hypoxia), has been shown that affects reproductive parameters in males [4–8]. However, this exposure and its effect on the prostate have yet to be evaluated in depth, despite high mountain sickness and prostate diseases sharing common factors.

On the one hand, in hypobaric hypoxia, the oxygen partial pressure in blood and tissues decreases and this reduction is sensed, generating a series of cardiovascular, cell and metabolic processes to maintain homeostasis [9–13], which activates genes and secondary messengers [14–18]. This condition affects the whole organism, and in some organs, such as the brain and lungs [19], could elicit brain (HACE) and pulmonary edema (HAPE), two severe complications to hypobaric hypoxia exposure, that can yield death [20, 21].

On the other hand, it has been reported that hypobaric hypoxia can affect several reproductive parameters, such as the reduction of fertility and virility in humans [18, 22–24]. Also, a hypoxic microenvironment in prostatic cancer cells can contribute to the tumor progression [25, 26]. Nevertheless, there is currently no evidence to support whether hypobaric hypoxia could positively or negatively affect prostate function.

This review attempts to address this question by summarizing research in the physiological responses to hypobaric hypoxic exposure and reproductive parameters, including prostate diseases, by presenting unsettled issues within the field using both clinical and basic scientific evidence.

Prostatic diseases: indicators and clinical manifestations

The prostate is a reproductive gland that contributes to the motility and nutrition of spermatozoids [27, 28]. The most frequent pathologies of this gland are prostatitis and benign prostatic hyperplasia (BPH), which are considered as benign conditions, and prostate cancer (PCa) considered as a grievous condition [29].

An enlarged prostate is associated with an unregulated proliferation of connective tissue, smooth muscle, and glandular epithelium. That compresses the urethra blocking the outflow of urine and origin anatomic bladder outlet obstruction (BOO) as a consequence [30]. The BOO may become apparent with lower urinary tract symptoms (LUTS), and LUTS is related to sexual dysfunction, including ejaculatory loss, painful ejaculation and erectile dysfunction [31]. Moreover, LUTS impact negatively on levels of prostate-specific antigen (PSA), a biomarker widely used in the diagnosis of prostate diseases [29, 31–33].

An elevated PSA in serum can suggest having a tumor in the prostate, but it can also be a signal of benign pathologies of the prostate [32]. Additionally, other factors such as age and comorbidities can also increase this gland volume [34–37].

In respect to hypobaric hypoxia and prostate, there is limited evidence to show an association. However, there have been investigations that reported the effect of HA on other male reproductive parameters.

Effects of hypobaric hypoxia on male reproductive parameters

Studies conducted in both animals and humans have reported the adverse effects of different hypoxia types in male reproductive parameters (Table 1).

Table 1.

Effects of hypobaric hypoxia on male reproductive parameters.

Parameter	Subjects of study	Type of hypoxia	Outcome	References
Testicular structure	Animals	* CCHH and ICHH	The height of the seminiferous epithelium decreased.	[38, 39]
	Humans	AHH	Hypoxic HA trekking reduced testicular volumes of both left and right testes.	[40]
Spermatogenesis, sperm count and sperm quality.	Animals	AHH, *AHH	Epididymal sperm count, sperm cell production, semen volume, and sperm motility were significantly reduced by acute and intermittent hypobaric hypoxia.	[41, 42]
	Humans	AHH	Physical exercise at high altitude reduced sperm concentration	[43]
		AHH	HA exposure by 1 year induce reversible effects on semen quality.	[44]
		CHH	HA affected sperm quality and DNA but effects were reversible	[45]
		AHH, CHH.	Reduction of sperm motility in acute and chronic exposure to high altitude.	[46, 47]
Virility & erectile dysfunction	Animals	* * CIH	Chronic intermittent hypoxia during sleep was associated with decreased libido in mice.	[48]
	Humans	CHH, AHH.	Erectile dysfunction	[49, 50]
		CHH	Nocturnal erection quality	[51]
Sexual hormone: testosterone	Animals	* CHH	Testosterone level decreased significantly after 30 days of chronic hypobaric hypoxia exposure in male Wistar rats.	[52]
	Humans	CHH	Testosterone is higher in men with excessive erythrocytosis (EE) at HA.	[53]*** [54]
Varicocele	Animals	* CHH	Hypobaric hypoxia increases testicular vascularization.	[39]
		By expression of HIF-1a	Left-side varicocele could cause epididymal hypoxia and epididymal dysfunction.	[22]
	Humans	Hypobaric hypoxia	* Germ cell apoptosis, DNA damage, oxidative stress and hormonal imbalances are common features in hypoxia and varicocele and testicular torsion.	[55]*** [57]***
		CIHH.	Higher prevalence of varicocele in miners working over 300 masl.	[58]
Prostatic illness	Humans	AHH	PSA values before and after exposure did not show significant difference.	[59]
		CHH	Lower concentration of PSA in residents over 4000 masl.	[60]

^*Hypobaric chamber.

^{* *}Chronic intermittent hypoxia CIH by OSAS.

^{* * *}Review paper.

Abbreviations: HA = high altitude; CCHH = continuous chronic hypobaric hypoxia; ICHH = intermittent chronic hypobaric hypoxia; AHH = acute hypobaric hypoxia; CHH = chronic hypobaric hypoxia; CIHH = chronic intermittent hypobaric hypoxia in miner population; HIF-1a = hypoxia-inducible factor-1a; PSA = prostate-specific antigen.

In rats, hypobaric hypoxia can affect the testes producing alteration in the spermatogenesis and the epididymal sperm count [4, 23]. This exposure also increases the testicular temperature, the seminiferous tubules’ diameter, and the spermatogenic epithelium’s height [61, 62]. In male climbers, the experience of long trekking at high altitudes can cause a reduction of testicular volume [6], a decrease of sperm concentration [63], sperm motility [64], and alterations in the integrity of nuclear DNA in semen [65].

Another abnormal function at the testicular level is varicocele, which is an abnormal dilatation and tortuosity of the internal spermatic veins within the pampiniform plexus of the spermatic cord. This illness is commonly associated with the malfunctioning of spermatogenesis, epididymal hypoxia, and epididymal dysfunction [66]. In rats, left-side varicocele causes epididymal hypoxia and epididymal dysfunction [22].

Changes in male reproductive hormones after HA exposure have also been observed. For example, testosterone (T), an androgen that is implicated in the maturation and preservation of male sexual organs [67, 68], has an essential role in the metabolism of people who are not well adapted to HA [69, 70]. In this case, serum testosterone concentration is higher than people who live at sea level [71]. Fortunately, exposure to HA has shown reversible effects on semen quality and serum reproductive hormone levels in young male adults [8].

Virility can also be affected by hypoxia. On the one hand, in a murine model, erectile dysfunction is caused by non-environmental chronic intermittent hypoxia (CIH) [72], which is a consequence of obstructive sleep apnea syndrome (OSAS) [28, 73]. Moreover, in men under hypobaric acute exposure, the penile rigidity decreased progressively with altitude, and this dysfunction has shown to reverse when returning to sea level [24, 74].

Finally, even though there is much scientific evidence related to the effects of any type of hypobaric hypoxia in sexual male parameters (Table 1), few studies had investigated the relationship between prostate and hypobaric hypoxia [5, 75]. One study showed lower PSA levels in males highlanders over 4000 masl than their counterparts at sea level [75], while other study carry out in climbers did not show significant differences in PSA levels before and after the trekking at very HA [5].

Although the physiological mechanism of this exposure on the prostate is still unclear, there are common factors in this relationship that could indicate a possible effect of this exposure on the prostatic physiology, and we will amplify it in the next section.

Common factors between hypobaric hypoxia exposure and prostatic diseases

The prostate, in abnormal conditions, can cause the activation of metabolic factors like the effect produced under hypobaric hypoxic exposure. These common factors are related to the hypoxic cell environment, inflammation, and endocrine metabolism.

One of the main elements secreted in cells in response to hypoxia are the hypoxic inducible factors (HIF-1α, HIF-2α) [76, 77]. These molecules are stabilized through different cofactors and pathways and subsequently translocated to the nucleus, heterodimerizing with HIF-1β, generating the transcription factors HIF-1 and HIF-2. Then, both together activate the transcription of genes via the hypoxia-response element (HRE) in their promoter region [76, 78–81].

In prostatic and high altitude diseases, the responses afterward transcription are the stimulation of angiogenesis, erythropoiesis, inflammation, vasoreactivity, and glucose metabolism [80–87]. In this sense, some authors point out that HIF-1α could be a target for prostatic illness and an independent risk factor for acute urine retention in benign prostatic hyperplasia patients because of chronic inflammation in the high proliferative prostate tissues [83, 88].

The sentrin-specific protease 1 (SENP-1) is another molecular protein that has been reported to get activated under hypoxic conditions such as chronic mountain sickness in Andean highlanders [89]. SENP1 plays important roles in maintaining the activity of HIF-2 during hypoxia, augmenting EPO, and erythropoiesis [90]. Furthermore, SENP-1 participates in the regulation of multiple cellular signaling pathways, including glucose and mitochondrial metabolism, hormone receptor activity, among others [90]. SENP-1 also increases the androgenic action and its expression in prostate diseases, improving tumor progression [91, 92].

Iron metabolism also has a parallelism with tumoral [93] and environmental [94] hypoxia. However, iron might be a protector factor. By increasing cellular iron, HIF-2a provides reactive oxygen species, which, coupled to posttranslational protein modification, can kill tumor cells [95]. Furthermore, inflammation has a crucial role in the pathophysiology and progression of prostatic and high altitude diseases [9, 11, 96–99]. It has been reported the increase of C-reactive protein (CRP) and interleukine-6 (IL-6) in prostatic diseases and mountain sickness [97, 100–102]. In literature is found that HIF-1α mediates prostate enlargement under inflammatory conditions [103], and prostate or bladder cancer are associated not only with inflammation but also with urinary symptoms and infection, [28]. Additionally, raised inflammatory markers in semen were positively associated with body mass index, PSA and estradiol levels but negatively associated with semen volume, total sperm count, and sperm motility [104]. Likewise, all the last-named male sexual parameters are also altered under hypobaric hypoxia.

Moreover, another common biomarker, which play a critical function in prostate illness and chronic mountain sickness (CMS) is testosterone. This androgen is responsible for the normal growth and function of the prostate and its alteration has a significant role in the acquisition of hallmarks of malignant diseases [105, 106]. In individuals with CMS, the testosterone levels are high, even more than people who live at HA without CMS or people who live at sea level [70, 71]. The early rise of testosterone in hypoxia acts as a vasodilation agent and a coactivator of the erythropoietic response in hypoxia, operating as a local paracrine signal toward bone marrow cells [72].

On the other hand, in epidemiology studies, the abnormally dilated veins in the pampiniform plexus named varicocele is frequent in the two mentioned illnesses. For instance, the prevalence of varicocele in mining workers exposed to chronic intermittent hypobaric hypoxia (CIHH) was higher in those who worked over 3000 masl compared to those who worked below 3000 masl [107], as well as in patients with increased total prostate volume and nocturia levels [108]. Even more, some authors consider the varicocele as the root cause of benign prostatic hyperplasia (BPH), and the varicocele treatment can reduce the prostate volume in more than 80% of cases [109]; moreover, some researchers suggest that hypobaric hypoxia, testicular torsion, and varicocele have a conjoint action mechanism at the testicular level by increasing reactive oxygen and nitrogen species (ROS/RNS) formation [72].

Just as the prostatic diseases, the hypobaric hypoxia or intermittent hypoxia caused by obstructive sleep apnea also affects erectile dysfunction in humans and animal models [28, 72–74]. In patients with obstructive sleep apnea, the lower urinary tract symptoms are frequently observed, and these symptoms are associated with prostate enlargement, bladder outlet obstruction, and altered seminal parameters in middle-aged men [104]. Moreover, in patients with chronic prostatitis living in HA areas, erectile dysfunction and premature ejaculation were positively correlated with the altitude [7].

Hypoxia and inflammation are constant characteristics of the prostate tumor microenvironment and HA illness [96, 110, 111]. The androgens might play an essential role in the prostate gland’s growth and function, and chronic hypoxia might exacerbate prostatic illness’s appearance.

A summary of the evidence of the common factor between hypobaric hypoxia and prostatic diseases appears in Table 2.

Table 2.

Common factors between hypobaric hypoxia exposure and prostatic illness.

	Prostate diseases	HA exposure
Parameter	Specimen	Effect	References	Specimen	Effect	References
Hypoxic inducible factor 1 (HIF-1)	Rat & human’ prostate cancer cell lines	↑HIF-1α mRNA	[60]	Cell culture: Tibetan PHD2 haplotype (D4E/C127S)	↑HIF-1α and HIF-2α in low habitants.	[87]
					↑HIF-1α in Tibetans
	Prostate tissues	↑HIF-1α	[113]	_	_	_
Sentrin-specific protease 1 (SENP-1)	Prostate tumor tissues	↑SENP-1	[114–116]	CMS cell culture	↑SENP-1	[117, 118]
Interleukin 6 (IL-6)	BPH & normal prostate specimens	↑IL-6	[119]	Serum samples	↑IL-6	[120, 121]
CRP	Serum samples	↑ CRP	[122].	Serum samples	↑ CRP	[123].
Testosterone (T)		↑T	[123].		↑T	[123, 124]
Spermatogenesis, sperm count and semen quality	Semen samples	↓Sperm concentration, sperm progressive motility and normal sperm morphology.	[125]	Semen samples	↓ Sperm concentration	[126, 127]
					↓ Sperm count	[128]
					↓ Sperm density
					Altered mtDNA copy number and nDNA integrity in the sperms.	[129]
Erectile dysfunction	Human patients	Positive association between ED and subsequent PCa incidence	[130]	Human patients	↓ Mean % of rigidity and rigidity time	[131]
					↓ Sleep-related erections (SREs)	[132]
					Premature ejaculation, erectile dysfunction, and difficult ejaculation.	[133]
Varicocele	Patients & plasma	Bilateral and/or higher-grade varicocele is associated with lower prostate
		Volume
		Bilateral and/or higher grade varicocele is associated with lower prostate
		Volume
		Bilateral and/or higher-grade varicocele is associated with lower prostate
		Volume
		Varicocele indirect cause the BPH	[134]	* Male Wistar rats	Hypoxia induced remodeling and proliferation of blood vessels in the testis.	[135]
		Varicocele is associated with lower prostate volume	[136]	Miners.	Higher prevalence of varicocele at HA	[137]
LUTS	Human Patients	↑BPH/LUTS prevalence and incidence rates	[138]	Male Sprague–Dawley rats	* * ↑HIF-1α and HIF-2β In (PBOO); LUTS/BPH.	[139]
Prostate-specific antigen (PSA)	Patients	↑PSA	[140, 141]	Humans’ climbers	No alterations PSA	[142]
				Humans’ volunteers	↓PSA	[143]

Abbreviation: PCa = prostate cancer; BPH = benign prostatic hyperplasia; PBOO = partial bladder outlet obstruction; mRNA = messenger RNA. ^*Hypobaric chamber;

^{* *}In non-hypobaric hypoxia conditions.

Hypobaric hypoxia and its possible effects on the prostate

The relationship between hypobaric hypoxia and prostatic illness has barely been explored, despite prostate diseases being among the most common and increasingly significant diseases worldwide [144, 145] and despite a considerable number of males living and working under this exposure [146–148]. Notwithstanding the paucity of evidence in this topic, a simplified and consistent approach to possible physiologic mechanisms is presented in five paragraphs in this section.

First, the activation of the hypoxia-inducible factor (HIF) inside the prostate cells, which is responsible for activating secondary messengers, inflammatory mediators, anti-apoptotic gene expression, angiogenesis, and aggressiveness in prostate tumor condition in hypoxic conditions [26, 149–153]. In normoxia, HIF1-α and HIF-2α are hydroxylated by prolyl hydroxylase domains (PHDs) and by asparaginyl hydroxylase, the latter called factor inhibiting HIF (FIH). Prolyl hydroxylation targets HIF-alphas for proteasomal degradation by binding to the von Hippel–Lindau (VHL) protein [151, 152] and HIF-alphas hydroxylation by FIH, prevents the binding with p300/CBP, transcriptional co-factors, preventing HIF the initiation of transcription under normoxia [154].

However, in hypobaric hypoxia plus the hypoxic condition inside the prostate tumor, HIF-α increases its availability, since the lower PO₂ reduces the PHD and FIH activities, and hamper HIF-α degradation by the proteosome and, in contrast, favors the binding p300/CBP, transcriptional co-factors, promoting HIF’s transcription under hypoxia. Then, within the nucleus, HIF-1α or HIF-2α joins HIF-1β, generating HIF-1 or HIF-2, respectively, transcription factors reacting with the hypoxia response element (HRE) region triggering the transcription of numerous genes, among them the vascular endothelial growth factor (VEGF), that it is associated with prostate cancer progression and metastasis [26].

We believe that additional cellular hypoxia accentuated by hypobaric hypoxia might promote that HIF-1α or HIF-2α, the latter more closely involved with red cell production enhancing the erythropoietin (EPO) transcription and erythropoiesis regulation [77, 90, 155], provoking a raising PSA’s levels in males exposed to HA chronically.

Second, the androgen imbalances [108] might also be involved in the HIF-α pathway mechanism for the expressions of prostate outcomes, due to testosterone plays an essential role in prostate growth, and it is increased in males with excessive erythrocytosis (EE) and CMS [156, 157]. In EE and CMS, the HIF-α escapes prolyl hydroxylation and undergoes SUMOylation, that is another mechanism to catabolize HIFs by the proteosome, observed during hypoxia. But sentrin/SUMO-specific protease 1 (SENP1), that it is increased in EE in CMS, deSUMOylate HIFs, allowing HIF-2 to have a longer half-life and therefore enhancing the polycythemia in CMS. Furthermore, SENP1 also deSUMOylate the androgen receptor (AR), allowing an augment in red cell production by AR, independent from HIF-2. In addition, SENP1 increases AR dependent transcription through its ability to deconjugate histone deacetylase 1 (HDAC1) [155]. On the other hand, in patients with BPH, testosterone or dihydrotestosterone (DHT) (the more active form of testosterone) [158] interacts directly with the androgen receptor bounded to the promoter region of androgen-regulated genes in the stromal cells, stimulating the proliferation [159], and intensifying the expression of HIF-1α target genes and PSA, similarly to the mechanism in cellular hypoxia in prostatic cancer cell lines (LNCaP) [160–163]. These coupled with the oxidative stress, inflammation, reduction of superoxide dismutase (SOD) and activation and nuclear translocation of NF-κB [164]. Thus, this too suggests that PSA levels would be increased at HA.

In addition, epidemiology studies showed a higher prevalence of varicocele in males with prostatic illness and in male workers at HA ratifying our hypothesis about testosterone flow might affect the prostate physiology at HA. Varicocele produces elevated pressure, diverting undiluted bioactive testosterone (FT) from the testes to the prostate. FT is more than 100 times normal serum levels, resulting in accelerated cell proliferation, leading to BPH development [165]. Moreover, the abnormally high rate of prostate cell production engenders DNA replication errors that can accumulate in subsequent cell generations, eventually resulting in critical mutations and, with time, prostate cancer cells. [109].

Third, in prostate cancer (PCa) cells, hypoxia increases the expression of histone demethylase O₂-dependent member of the Jumonji protein family (JMJD1A) or the plant homeo domain finger protein 8 (PHF8), which also modifies the histone tails through its demethylase activity in the promoter regions of AR target genes and enhances AR targets’ expression [166] of transcriptional activators in response to androgens [167]. In this point, SENP1 reverses the hormone augmented SUMOylation of AR might increase the transcription activity of AR in the same manner that in CMS [89]. Furthermore, SENP1 also rescues the HIF-α from polyubiquitination and degradation allowing its association with nuclear HIF α [90], and the upregulation of SENP1 expression might increase available deSUMOylated GATA-1, a transcription factor capable to increase EPO receptors, augmenting further the erythropoiesis in hypoxia and CMS [90].

Once more, according to this information in both conditions, the AR activity might increase PSA promoter occupancy of the androgen response element (ARE) region of the PSA gene [168] and interacts with the angiogenic pathway [169] through SENP1 and GATA factors. Moreover, hypoxia and androgen additively might increase the recruitment of JMJD1A and p300 on PSA’s enhancer region through interaction with the HIF-1α and AR [170]. Thus, these mechanisms suggest that in males with CMS and high levels of T, the prostate metabolism could accelerate the gland’s enlargement, which is a characteristic of prostatic illness.

Fourth, an increase in reactive oxygen species (ROS) probably owed to mitochondrial dysfunction along with activation of the inducible nitric oxide synthetase (iNOS) by hypoxia [171], may also increase the HIFs production. The NO inactivation after the increased ROS production through activation of the inducible NO synthase (Nos2) gene promoted by HIF-1α [172], whereas HIF-2α inhibits NO production through the induction of the arginase (Arg) gene [148].

Fifth, the induction of proinflammatory cytokines is probably part of the response mechanism in prostate cells in those exposed to HA as well as the hypoxic testicle [72]. Besides, hypoxia in PCa cells enhances the transcriptional activity of AR and promotes the overexpression of VEGF-A through HIF-1α via regulation of epidermal growth factor receptor (EGFR) expression and upregulation of cytokines (mainly IL-6) [169] notable for their role in driving PCa progression and metastasis [26]. As well as in high-altitude pulmonary edema (HAPE), circulating IL-6 and CRP are upregulated in response to hypobaric hypoxic conditions at HA [111].

Finally, living at HA was associated with a higher prevalence of cancer and increased risk of death by cancer [173]. In contrast, some authors affirm that cancer mortality declines with increasing altitude by the sum of adaptive processes [174]. Other factors such as genetic, bacterial, dietary, and environmental may cluster in some mountainous regions [175] (Figure 1).

Figure 1.

Proposed hypothesis for the mechanism whereby hypobaric hypoxia affect prostate function. Approach of mechanism five steps: 1) HIF-α activation by hypoxic conditions (ROS, testosterone and environmental) [108, 113, 134]. 2) Androgen action through AR and activation of HIF target genes and PSA [112, 114]. 3) The PHF8 activate the promoter region ARE by SENP1 increase available deSUMOylated GATA-1 and enhance PSA gene transcription [63, 69]. 4) ROS and NO inactivation promoted by HIF-1α whereas HIF-2α inhibits NO production. 5) Hypoxia enhances the transcriptional activity of AR and promotes the overexpression of VEGF-A through HIF-1α and EGFR expression and upregulation of IL-1β, IL-6 and CRP [108, 113].

Summary and conclusion

In summary, the androgen receptor in the prostate of males exposed to high altitude might enhance HIF-1-mediated gene expression and interact with the histone demethylases on the PSA gene promoter and activates its expression similarly to prostate cancer tissue [176].

The lack of epidemiological studies that report the incidence of prostate diseases in high-altitude cities adds another gap to this relevant issue, particularly in a scenario of exposure related to work associated with mining activities. This situation could be more damaging in those who are not well adapted to living and working under hypobaric hypoxia. Epidemiological surveillance as an occupational health tool is essential to identify if hypobaric hypoxia is a new risk factor for prostate disease, opening a field of research in public health. More studies related to this topic will also contribute to the possibility of understanding prostatic cancer pathogenesis and help unravel the role of aging, another hypoxic condition, in prostate disease.

Data availability

No original data were reported in this work.

Author contributions

DEA-Z wrote the first draft of the paper that was edited by A.J.L. and C.N. DEA-Z, contributed to figures and tables. A.J.L. and C.N. contributed to manuscript writing and revision. All authors read and approved the final version of the manuscript.

Abbreviations

AR: Androgen receptor

ARE: Androgen response elements

BPH: Benign prostatic hyperplasia

CIH: Chronic intermittent hypoxia

CMS: Chronic mountain sickness

CRP: C-reactive protein

DHT: Dihydrotestosterone

EE: Excessive erythrocytosis

EGFR: Epidermal growth factor receptor

EPO: Erythropoietin

GATA: The GATA-binding proteins are a group of structurally related transcription factors that bind to the DNA consensus sequence GATA

HA: High altitude

HIF: Hypoxia inducible factor

HRE: Hypoxia response element

IL-1β & IL-6: Interleukin-1β and Interleukin-6

LUTS: Lower urinary tract symptoms

NO: Nitric oxide

OSAS: Obstructive sleep apnea syndrome

PHDs: Prolyl hydroxylase domain

PHF8: Plant homeo domain finger protein 8

PO₂: Partial pressure of oxygen

PSA: Prostate-specific antigen

SENP1: Sentrin/SUMO-specific protease1

T: Testosterone

VEGF-A: Vascular endothelial growth factor A

Conflict of interest

The authors have no conflict of interest.