1. X Chromosome Number and Structural Anomalies

The most common numerical anomaly is Turner syndrome, characterized by a karyotype of 45, X and its variants. Clinical manifestations typically include lack of secondary sexual characteristics, primary amenorrhea, infertility, underdeveloped breasts, and sparse or absent pubic and axillary hair. Multiple X syndrome, including triple X syndrome and the rarer tetra X or penta X syndromes, may also be associated with menstrual irregularities, recurrent miscarriages, and infertility. Structural anomalies commonly involve breakpoints in the critical region of Xq21.1-22.3.

2. Autosomal Chromosome Number and Structural Anomalies

Autosomal numerical abnormalities mainly include polyploidy, chimerism, and trisomy syndromes. Polyploid fetuses often struggle to survive, while chimerism refers to the presence of two or more different chromosome count cell populations in an individual, resulting from failures in chromosome separation or loss during cell division. Trisomy syndromes are generally caused by unequal separation during the first or second meiotic divisions of sperm and eggs, particularly the latter, and are related to advanced maternal age. Autosomal structural abnormalities typically arise from chromosome breakage followed by deletions, duplications, inversions, translocations, and even the formation of isochromosomes, ring chromosomes, or dicentric chromosomes, all of which can cause infertility.

3. Single Gene Disorders

Female infertility due to single gene diseases can occur at different levels of the hypothalamic-pituitary-gonadal axis, potentially affecting sex determination, development, and gonadal function (including hormone synthesis and fertility).

  • Hypothalamic gene mutations: The hypothalamus secretes gonadotropin-releasing hormone (GnRH) in a pulsatile manner. Mutations in related genes at the hypothalamic level leading to a deficiency of gonadotropins can result in hypogonadism and ultimately infertility. Relevant mutation genes primarily include KAL1, NR0B1, LEP, and LEPR.
  • Pituitary level gene mutations: Gene mutations at the pituitary level include those affecting the GnRH receptor and gonadotropin genes, which cause reduced gonadotropic hypogonadism.
  • Genes causing premature ovarian failure (POF): Patients with POF have a higher rate of chromosomal abnormalities, with incidences ranging from 16% to 21%. POF-related genes are inherited in an autosomal or X-linked dominant manner. Autosomal gene mutations include those in the FSH gene and its receptor, typically presenting with primary amenorrhea and ovarian failure. X chromosome gene mutations are the most common cause of POF, often inherited maternally. Mutations on the short arm of the X chromosome (Xp), such as those causing Turner-like syndrome, include the bone morphogenetic protein 15 (BMP15) gene located at Xp11.22, which is involved in ovarian growth and differentiation and related to granulosa cell proliferation, serving as an FSH-dependent oocyte-specific regulatory factor. Paternally derived BMP15 mutations are associated with familial ovarian failure.