Mechanisms of Obesity-induced Male Infertility

Karen P Phillips; Nongnuj Tanphaichitr

Disclosures

Expert Rev Endocrinol Metab. 2010;5(2):229-251. 

In This Article

Spermatogenesis & the Assessment of Male Fertility

Testicular function is regulated by the hypothalamic–pituitary–testicular (HPT) axis (Figure 1). Gonadotropin-releasing hormone (GnRH) is released by hypothalamic neurons and stimulates the release of pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH),[2] both of which play major roles in the regulation of testicular steroidogenesis and spermatogenesis, respectively (Figure 2). The mature spermatozoa (sperm) are polarized cells, each consisting of a head, midpiece and tail (Figure 3). These structural entities of sperm are used as landmarks for morphological categorization. Testicular injury, disease or impairments of the HPT axis can produce abnormalities of spermatogenesis with consequences, including the production of fewer, abnormal or underdeveloped sperm, characterized by morphological defects or reduced motility. Further modifications of biochemical and kinetic properties of sperm take place in the female reproductive tract; a process known as capacitation, which includes the acquisition of hyperactive motility (Figure 4).[6,7] Once bound and penetrating the egg zona pellucida, sperm undergo the zona pellucida-induced acrosome reaction (Figure 3), an acrosomal exocytosis event that involves the release of hydrolytic acrosomal enzymes, followed by fusion of one of these acrosome-reacted sperm with the egg plasma membrane and sperm incorporation into the egg (fertilization).

Figure 1.

Hypothalamic–pituitary–testicular axis. Systemic regulation of testicular function is provided by the hypothalamic–pituitary–testicular axis. Briefly, the hypothalamus releases GnRH, which acts on the anterior pituitary to release FSH and LH. FSH binds to receptors on testicular Sertoli cells to regulate spermatogenesis. LH binds receptors on testicular Leydig cells.
FSH: Follicle-stimulating hormone; GnRH: Gonadotropin-releasing hormone; LH: Luteinizing hormone; T: Testosterone.

Figure 2.

Mammalian spermatozoa. Spermatogenesis is supported by Sertoli cells contained within testicular seminiferous tubules. Spermatogonium (type A) continuously replicates by mitosis. Spermatogonium (type B) undergoes mitosis followed by two rounds of meiosis to produce spermatocytes and spermatids. Round spermatids undergo differentiation (spermiogenesis) including remodeling of the cytoplasm to form elongated spermatids and ultimately testicular spermatozoa. Major stages include: spermatogonium type A and type B; primary spermatocyte (shown pachytene spermatocyte); secondary spermatocyte; round spermatid; elongated spermatid; and testicular spermatozoa.

Figure 3.

Mature spermatozoon undergoes the acrosome reaction upon binding to the egg's extracellular matrix, the zona pellucida. Featured on the left is a mature spermatozoon with three morphological structures: head, midpiece and tail. The head contains the acrosome and the nucleus. The midpiece is the 'engine' of the spermatozoon, densely packed with mitochondria that power the flagellum or tail. Spermatozoa initially lack the ability to fertilize an egg, necessitating further remodeling (capacitation) induced by contact with the female reproductive tract. Capacitation is accompanied by cholesterol efflux, protein tyrosine phosphorylation and rupture of the acrosomal membrane, releasing acrosomal enzymes (acrosome reaction), as shown on the right. Acrosome reaction involves fusion of outer acrosomal membrane with sperm plasma membrane, progressive loss of outer acrosomal membrane and acrosomal contents and, finally, exposure of the inner acrosomal membrane.

Figure 4.

Sperm capacitation signaling. The process of capacitation includes changes to the sperm membrane and the acquisition of hyperactive motility. Hallmark characteristics of sperm capacitation including intracellular increases in cAMP and HCO3 , cholesterol efflux and tyrosine phosphorylation. Ob-R signal crosstalk is also shown (see text for details). Dotted lines indicate proposed pathways and solid lines indicate established pathways.
cAMP: Cyclic adenosine monophosphate; EGFR: EGF receptor; ERK: Extracellular signal-regulated kinase; JAK: Nonreceptor tyrosine kinase; MEK: Mitogen-activated protein kinase; PDE: Phosphodiesterase; PKA: Protein kinase A; SACY: Soluble adenylyl cyclase; Y-P: Phosphorylated tyrosine residue.

The determination of spermatozoa concentration, morphology and motility remains the primary clinical tool for the assessment of male infertility.[8] Reproductive hormone profiles (free and total testosterone, estradiol, LH and FSH) in addition to semen parameters are typically used to assess male reproductive function. Development of clinical assays to delineate new parameters that better reflect sperm fertilizing competence are needed.

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