Physical activity counteracts metabolic syndrome-induced hypogonadotropic hypogonadism and erectile dysfunction in the rabbit
Abstract
Metabolic syndrome (MetS) clusters cardiovascular and metabolic risk factors along with hypogonadism and erectile dysfunction. Lifestyle modifications including physical exercise (PhyEx) are well-known treatments for this condition. In this study, we analyzed the effect of PhyEx on hypothalamic-pituitary-testis axis and erectile function by use of an animal MetS model, previously established in rabbits fed a high-fat diet (HFD). Rabbits fed a regular diet (RD) were used as controls. A subset of both groups was trained on a treadmill. HFD rabbits showed typical MetS features, including HG (reduced T and LH) and impairment of erectile function. PhyEx in HFD rabbits completely restored plasma T and LH and the penile alterations. At testicular and hypothalamic levels, an HFD-induced inflammatory status was accompanied by reduced T synthesis and gonadotropin-releasing hormone (GnRH) immunopositivity, respectively. In the testis, PhyEx normalized HFD-related macrophage infiltration and increased the expression of steroidogenic enzymes and T synthesis. In the hypothalamus, PhyEx normalized HFD-induced gene expression changes related to inflammation and glucose metabolism, restored GnRH expression, particularly doubling mRNA levels, and regulated expression of molecules related to GnRH release (kisspeptin, dynorphin). Concerning MetS components, PhyEx significantly reduced circulating cholesterol and visceral fat. In multivariate analyses, cholesterol levels resulted as the main factor associated with MetS-related alterations in penile, testicular, and hypothalamic districts. In conclusion, our results show that PhyEx may rescue erectile function, exert anti-inflammatory effects on hypothalamus and testis, and increase LH levels and T production, thus supporting a primary role for lifestyle modification to combat MetS-associated hypogonadism and erectile dysfunction.
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HFD rabbits showed typical metabolic and cardiovascular features of metabolic syndrome along with hypogonadotropic hypogonadism.
“As mentioned before, HFD rabbits showed typical metabolic and cardiovascular features of MetS along with hypogonadotropic HG.”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [62]
In the testis of MetS rabbits, all steroidogenic enzymes leading to testosterone synthesis were downregulated in a stepwise fashion, and fibronectin expression was increased.
“Within the testis, the MetS condition down regulated, in a stepwise fashion, all the steroidogenic enzymes leading to T synthesis, along with an increase in fibronectin expression.”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [62]
Upon high-fat diet, genes coding inhibitory factors for GnRH were increased, as well as neuropeptide Y and prodynorphin, along with their cognate receptors.
“We previously reported that, upon HFD, genes coding inhibitory factors for GnRH were increased, as well as neuropetide Y and prodynorphin, along with their cognate receptors [62].”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [62]
In the hypothalamus, physical exercise increased Kiss1 and decreased orexigenic and GnRH-inhibiting factors (dynorphin and its receptors OPRD1 and OPRK1), whereas it increased anorexigenic factors (proopiomelanocortin).
“In particular, in the hypothalamus, PhyEx increased Kiss 1 and decreased orexigenic and GnRH-inhibiting factors (dynorphin and its receptors OPRD1 and OPRK1), whereas it increased anorexigenic ones (proopiomelanocortin).”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [62]
In corpora cavernosa extracts, several genes related to NO formation (DDAH1) and signaling (GCSa1, GCSb1, PDE5, PKG) were up-regulated by physical exercise, along with those involved in smooth muscle differentiation (SM22, αSMA) and androgen action (AR, STAMP2).
“In CC extracts, several genes related to NO formation (DDAH1) and signaling (GCSa1, GCSb1, PDE5, PKG) were up-regulated by PhyEx, along with those involved in smooth muscle differentiation (SM22, αSMA) and androgen action (AR, STAMP2).”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [62]
HFD-induced increases in genes related to inflammation, estrogen signaling, and glucose metabolism in the hypothalamus were significantly reduced in HFD rabbits given physical exercise.
“All the aforementioned HFD-induced increase in genes related to inflammation, estrogen signaling, and glucose metabolism in the hypothalamus were significantly reduced in HFD+PhyEx.”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [62]
Physical exercise reverted all these alterations in corpora cavernosa.
“PhyEx reverted all these alterations.”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [62]
Physical exercise increased the ratio of androstenedione to testosterone concentration within the testis, which was downregulated by HFD.
“Accordingly, PhyEx increased the ratio of androstenedione to T concentration within the testis, which resulted downregulated by HFD [62].”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [62]
Corpora cavernosa strips from HFD rabbits showed hypo-responsiveness to acetylcholine and electrical field stimulation, and sildenafil action on electrical field- or sodium nitroprusside-induced relaxation was impaired in HFD corpora cavernosa.
“Corpora cavernosa (CC) strips from HFD rabbits showed a hypo-responsiveness to Ach and electrical field (EF) stimulation.”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [62]
Physical exercise completely restored testosterone and LH plasma levels, prostate weight and GnRH immunostaining in HFD rabbits, and doubled GnRH gene expression in the preoptic area.
“PhyEx completely restored T and LH plasma levels, prostate weight and GnRH immunostaining (Fig. 5), doubling its gene expression in the preoptic area [62].”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [62]
Within the testis, physical exercise normalized fibronectin expression and increased genes related to testosterone formation (17βHSD3) and metabolism (5α-reductase 1).
“Within the testis, PhyEx normalized fibronectin expression and increased genes related to T formation (17βHSD3) and metabolism (5α-reductase 1) [62].”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [62]
Physical exercise restored Kiss1 receptor immunostaining, which was decreased by HFD.
“PhyEx restored Kiss1 receptor immunostaining, which resulted decreased by HFD (Fig. 6B).”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [62]
The distinction between a functional and an organic form of hypogonadism is captious because even diet-induced hypogonadotropic hypogonadism is associated with distinct organic alterations within the hypothalamus, the testis and the penis.
“The distinction between a functional and an organic form of HG is, in some ways, captious because, as demonstrated in our preclinical model, even diet-induced hypogonadotropic HG is associated with distinct, organic alterations within the hypothalamus, the testis and the penis [606162].”
From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [62]
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Self-citation
- Authors
- Morelli, A., Filippi, S., Comeglio, P., Sarchielli, E., Cellai, I., Pallecchi, M., Bartolucci, G., Danza, G., Rastrelli, G., Corno, C., Guarnieri, G., Fuochi, E., Vignozzi, L., & Maggi, M.
- Affiliations
- University of Florence (IT)
- Istituto Nazionale Biostrutture e Biosistemi (IT)
- Corresponding author
- Maggi, Mario
- ORCID
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2019-03-01
- Volume
- 316
- Issue
- 3
- Pages
- E519-E535
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2909433309
- Cited by
- 59
- References
- 62
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 5 · 2023: 7 · 2022: 7 · 2021: 11 · 2020: 11 · 2019: 6
- FWCI
- 8.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- metabolic syndrome, hypogonadotropic hypogonadism, erectile dysfunction, physical activity, high-fat diet, hypothalamic-pituitary-testis axis, gonadotropin-releasing hormone, testosterone production, testicular inflammation, macrophage infiltration, steroidogenic enzymes, kisspeptin, dynorphin, hypothalamic inflammation, glucose metabolism, cholesterol, visceral fat, rabbit model
- MeSH terms
- Animals, Blood Glucose, Cholesterol, Dynorphins, Hypogonadism, Hypothalamo-Hypophyseal System, Erectile Dysfunction, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Macrophages, Male, Physical Conditioning, Animal, Rabbits, Testis, Testosterone, Triglycerides, Tumor Necrosis Factor-alpha, Metabolic Syndrome, Kisspeptins
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