Back to Main Sexual Health & Guidance

Sperm Production

Provided by National Institute of Child Health & Human Development

Overview

The male reproductive system encompasses the anatomical structures and physiological functions that produce mature sperm. This system has two theoretically distinct, but interrelated, aspects: fertility and virilization ("maleness"). To briefly summarize, the processes of sex determination and embryonic development produce a male child, setting the stage for the virilization and onset of fertility that begin with puberty. As with female reproduction, the brain, specifically the hypothalamus, signals the pituitary gland to secrete LH and FSH in a pulsatile pattern characteristic of adulthood. LH and FSH have specific functions in the testis. FSH stimulates male germ cells to develop into mature sperm, a process called spermatogenesis. LH stimulates testis accessory cells, called Leydig cells, to produce sex steroids, especially testosterone, through the process of steroidogenesis. Male hormones are needed for optimal sperm production, as well as for sexual function, healthy blood and bones, and general well being.

Sperm Production

Androgen and sperm maturation: For an estimated 40% of the 2.6 million infertile married couples in the United States, male factor infertility plays at least a contributing role. Only a small percentage of these male factor cases can be attributed to a treatable medical condition. Most infertile men are not given a definite diagnosis. In many cases, the male is normally virilized, but the testes make only immature male germ cells. These cells begin to develop but do not mature into sperm capable of fertilizing an egg. It is not known why the early germ cells fail to enter the cellular and chromosomal divisions, known as meiosis, that are required for maturation. Since androgen levels are normal, one important question is whether androgen action is required for meiosis. Androgens are known to act in the testis by binding to receptors on Sertoli cells and Leydig cells, but it remains controversial whether androgen receptors are needed or even present on germ cells.

Dr. Michael Griswold of Washington State University has studied this question using an X-linked mouse mutation that abolishes expression of the androgen receptor, so androgens cannot act. As a result, males appear female although they have internal testes. Dr. Daniel Johnston, a fellow in the Griswold lab, used a powerful new technique to transplant germ cells from males with this mutation, as well as a visible marker, into normal mice whose sperm production had been artificially suppressed. The transplanted cells were able to colonize the host testes and undergo meiosis, showing that the androgen receptor is not necessary for meiosis in early male germ cells. The explanation for maturation arrest in this model is not failure of direct androgen action, and must be sought elsewhere.

Spermatogenesis: Sperm cells develop from spermatogonial stem cells in the testis. These stem cells continuously renew themselves, reproducing by mitosis throughout almost the entire lifetime of human males. They can also enter a differentiation pathway leading to the formation of mature sperm. Maintenance of a large pool of mitotically active spermatogonial stem cells provides a renewable resource for optimal fertility over time. Much effort has been focused on genes on the male specific Y chromosome that control spermatogenesis. However, a new study by Dr. David Page and co-workers indicates that the X chromosome may also be an important target. In a systematic search for genes expressed only in spermatogonia (the self-renewing, mitotic germ cells), they identified 25 genes, 10 of which are X-linked.

Spermiogenesis: Spermiogenesis is the process through which round spermatids mature into spermatozoa, fully mature sperm capable of swimming. Dr. Patricia Morris and co-workers studied the role TRF-2, a transcription regulator, and surprisingly found that it has a very specific role in spermiogenesis. Male mice lacking the Trf-2 gene are normal and healthy, except for small testes. These males are infertile due to the failure of round spermatids to develop into elongated spermatids. Coincident with this block, there was reduced expression of post-meiotic genes, including those encoding the transition proteins and protamines that help condense chromatin. Therefore, Trf-2 may regulate round spermatid differentiation by selectively activating specific transcription of downstream genes.

Chromatin packing in spermiogenesis: Dramatic morphological changes take place in spermiogenesis, including the remarkable condensation of chromatin to pack it into the compact sperm head. Normal chromatin is loosely coiled around a complex of proteins called histones. To facilitate the condensation necessary for spermiogenesis, the histones are removed and replaced by small, basic, transition nuclear proteins (TP), which are in turn replaced by highly basic protamines.

Mice and humans are somewhat unusual among mammals in having two different protamines, Prm1 and Prm2. Dr. Norman Hecht's laboratory created mice that lacked one copy of either Prm1or Prm2 to see if both copies of both protamines are necessary for normal fertility. They found that decreasing either protamine disrupted nuclear structure and processing of protamine-2, and reduced sperm motility. Thus, both protamines must be present in normal amounts for proper sperm function and fertility. Regulation of protamine translation is critical for fertility. Protamine transcripts are made in round spermatids, but not translated until the elongating spermatid stage. Premature translation of Prm1 RNA causes early nuclear condensation, blocking spermatogenesis at the round spermatid stage. Now Dr. Robert Braun and colleagues have shown that a highly conserved sequence in the 3' untranslated region of the Prm1 messenger RNA is solely responsible for regulating its translation. Alterations in the translation control element of Prm-1mRNA are thus a possible cause of infertility in men lacking mature spermatozoa.