Y-chromosome structural changes may explain some cases of male infertility
image: Examples of histological sections of testicular biopsies from 2 patients with Y-chromosome structural re-arrangements. No mature spermatids or spermatozoa were observed in any of the examined seminiferous tubules, indicating complete spermatogenic arrest.
Credit: Hoa Thi Phuong Bui; Viet Huu Dinh; Cuong Kien Trinh; Ngoc Minh Pham; Kien Van Nguyen; Trang Thi Huyen Nguyen.
For some men with severe infertility, standard genetic tests provide no clear explanation. A test may show that the Y chromosome has not lost any of its best-known fertility genes, yet sperm production remains severely impaired. New research suggests that the problem may sometimes lie not in missing genetic material, but in how that material is arranged.
A study published in Reproductive and Developmental Medicine examined rare structural changes in the Y chromosome among men receiving reproductive care at the Andrology and Fertility Hospital of Hanoi, Vietnam.
The Y chromosome carries genetic instructions needed for sperm production. During the formation of sperm, chromosomes must align and separate in a highly coordinated process. If part of the Y chromosome has moved to another chromosome, flipped direction or formed an abnormal structure, that coordination may be disrupted, even when important fertility genes are still present.
The researchers reviewed genetic records from more than 21,000 men and identified 21 with structural Y-chromosome abnormalities. Most showed some degree of impaired sperm production. The most severe cases were frequently associated with exchanges of genetic material between the Y chromosome and another chromosome.
Importantly, routine testing found no deletions in the azoospermia factor, or AZF, regions among the men who produced no detectable sperm. AZF testing is commonly used to investigate severe male infertility, but the findings indicate that a normal result may not reveal every genetic problem affecting sperm development.
“A normal AZF result does not necessarily mean that the Y chromosome is functioning normally,” said corresponding author Hoa Thi Phuong Bui. “Changes in chromosome structure may still interfere with the biological process required to produce mature sperm.”
Four men underwent microdissection testicular sperm extraction, a procedure that searches testicular tissue for small areas of sperm production, but no sperm were recovered. This information could help clinicians give patients more realistic expectations before they undergo an invasive procedure.
The outlook was not uniformly negative. When sperm and embryos could be obtained, several couples achieved live births following embryo transfer.“A Y-chromosome rearrangement does not automatically rule out successful assisted reproduction,” Bui said. “The appropriate path depends on whether sperm can be obtained, whether viable embryos can be created and the specific genetic risks involved.”
The results support offering chromosome analysis and genetic counselling to men with unexplained absence of sperm or severely impaired sperm production, including those whose AZF tests are normal. Such evaluation may guide decisions about surgical sperm retrieval, assisted reproduction, embryo testing and alternative family-building options. Because the study included only a small number of affected men, larger investigations are needed before outcomes can be predicted for individual patients.