Reproductive Biology

Male fertility relies initially on proper formation and maintenance of seminiferous tubules – the site of spermatogenesis. Sertoli cells are specialized somatic cells within seminiferous tubules that are essential for sperm production.

Sertoli cell – Sertoli cell signaling

Proper Sertoli cell – Sertoli cell signaling is critical to maintaining seminiferous tubule architecture as well as the blood-testis barrier (BTB). Formed by tight junctions and adherens junctions between Sertoli cells, the BTB creates a specialized environment for spermatogenesis that provides nutritional support while protecting developing germ cells from toxins and potential attacks by the immune system. 

Multiple signaling pathways contribute to tight junction – adherens junction dynamics, but three are noted for their dominance: the transforming growth factor-β (TGF-β)/SMAD signaling pathway, the AMP-activated protein kinase (AMPK) signaling pathway and the mitogen-activated protein kinases (MAPK) signaling pathway (1). TGF-β/SMAD signaling additionally plays a role in Sertoli cell proliferation along with AMPK signaling which additionally supports lactate production – an important energy source for developing sperm.

Germ cell – Sertoli cell signaling

Once a proper environment for spermatogenesis is established, male fertility becomes reliant on Sertoli cell – germ cell signaling.

Both endocrine and paracrine signals contribute to spermatogenesis (2). The main endocrine signals, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) act on Sertoli cells to support spermatogenesis. Paracrine signaling relies upon a wide range of proteins including cadherins, catenins, integrins and focal adhesion kinase (FAK).

Sperm motility

Initially immobile, sperm acquire motility – a key requirement for navigation through the female reproductive tract – as they mature during transit through the epididymis.

Multiple signaling pathways activate motility, many of which are regulated by intracellular levels of the second messenger calcium (Ca²⁺). Influenced by Ca²⁺, potassium (K⁺), chloride (Cl^-), sodium (Na⁺) and hydrogen (H⁺) channels, increasing levels of Ca²⁺ leads to activation of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase pathway which activates protein kinase A (PKA) and its downstream targets (3). An overall shift from phosphatase activity to kinase activity is associated with induction of motility.

In addition to reaching the egg, spermatozoa must undergo capacitation – a process of physiological change that occurs within the female reproductive tract and prepares spermatozoa to penetrate and fertilize the egg. Changes in intracellular Ca²⁺ levels, in combination with changes in bicarbonate (HCO₃^-) levels, once again activate PKA which combines with activated protein kinase C (PKC) to influence final maturation (4). Ca²⁺ additionally binds to calmodulin within the head and flagellum of the sperm, activating calmodulin kinase which leads to hypermotility.

Notably, changes within the spermatozoa’s membrane composition prepare it for the acrosome reaction – a fusion of the specialized acrosome organelle with the head of the sperm that is required for penetration of the egg’s zona pellucida and fusion with its plasma membrane. Sulfated glycoproteins ZP1, ZP2, ZP3 and ZP4 which compose the zona pellucida interact with capacitated spermatozoa, facilitating the acrosome reaction (5).

Disruption to any of the above cellular processes can have a significant impact on male fertility with effects ranging from altered testicular architecture, including testicular atrophy, to disruption of spermatogenesis that results in low sperm count (oligospermia) or absence of sperm (azoospermia).

Treating erectile dysfunction

Although not directly related to fertility, Erectile Dysfunction (ED), also known as impotence, affects a large segment of the male population.

Generating and maintaining an erection requires a careful balance between the generation and breakdown of cGMP (6). Male sexual stimulation results in diffusion of nitric oxide (NOS) into cells where it activates soluble guanylyl cyclase to convert GTP to cGMP, resulting in activation of protein kinase G (PKG) and a downstream signaling cascade that triggers dilation of arteries that provide blood to the penis and compress the corpus cavernosum. Phosphodiesterase 5 (PDE5) acts to breakdown cGMP, reversing the effect. Blocking PDE5 activity in the corpus cavernosum through inhibitors such as Sildenafil (Viagra) produces an effect similar to sexual stimulation.

In addition to treating ED, PDE5 inhibitors are used to treat pulmonary hypertension and certain urological disorders. Potential additional cardiovascular, anticancer and neurological applications are being studied.  

References

1. Ni F, Hao S, Yang W. Cell Death Dis. 2019;10(8):541. doi: 10.1038/s41419-019-1782-z
2. Ruthig VA, Lamb DJ. Front Endocrinol (Lausanne). 2022;13:897196. doi: 10.3389/fendo.2022.897196
3. Pereira R, Sá R, Barros A, Sousa M. Asian J Androl. 2017;19(1):5–14. doi: 10.4103/1008-682X.167716
4. Delgado-Bermúdez A, Yeste M, Bonet S, Pinart E. Int J Mol Sci. 2022;23(11):6333. doi: 10.3390/ijms23116333
5. Siu KK, Serrao VHB, Ziyyat A, Lee JE. J Cell Biol. 2021;220(10):e202102146. doi: 10.1083/jcb.202102146
6. Samidurai A, Xi L, Das A, Kukreja R. Annu Rev Pharmacol Toxicol. 2023;63:585–615. doi: 10.1146/annurev-pharmtox-040122-034745