Testicular Dysgenesis

How the testes normally develop

In early pregnancy, the gonads are identical in all embryos. In embryos with a Y chromosome, the SRY gene and a cascade of other genes trigger the gonads to become testes, around weeks 6 to 7. The testes then make:

• testosterone, which develops the penis, scrotum and male internal ducts
• anti-Mullerian hormone (AMH), which prevents a uterus from forming
• INSL3, which helps the testes descend into the scrotum

Dysgenesis occurs when this process is disrupted.

Types

Complete 46,XY gonadal dysgenesis (Swyer syndrome)

People have XY chromosomes but gonads that are streak-like bands of tissue producing no hormones. They are born with typical female external genitals and a uterus, and are usually raised as girls. It is often diagnosed in the teens when puberty and periods do not start. The streak gonads carry a high risk of germ cell tumors and are usually removed.

Partial and mixed gonadal dysgenesis

The gonads are partly formed, or one is a testis and the other a streak (mixed gonadal dysgenesis, often 45,X/46,XY mosaicism). Genitals may look atypical at birth. Growth may be affected.

Testicular dysgenesis syndrome (TDS)

Proposed in 2001, TDS links four conditions thought to share a common origin in subtle fetal testis dysfunction:

• undescended testes (cryptorchidism)
• hypospadias, where the urethral opening is on the underside of the penis
• reduced sperm counts and quality in adulthood
• testicular germ cell cancer

Genetic factors and possibly prenatal exposure to chemicals that disrupt hormones (such as some phthalates), maternal smoking and other environmental factors are thought to contribute. The concept is widely discussed but the evidence for specific environmental causes is still debated.

Causes

• gene variants affecting testis development: SRY, NR5A1 (SF1), MAP3K1, DHH, WT1 and others
• chromosome variations: 45,X/46,XY mosaicism and other sex chromosome differences
• syndromes such as Denys-Drash and Frasier syndromes (WT1), which also affect the kidneys
• possible environmental factors in TDS

Signs and symptoms

• atypical genitals at birth
• undescended testes, on one or both sides
• hypospadias
• small testes
• delayed or absent puberty
• short stature in mosaic forms
• infertility or low sperm count in adulthood

Diagnosis

Children and families are best cared for by a specialist difference of sex development (DSD) team including pediatric endocrinology, urology, genetics and psychology.

• physical examination of the genitals and gonads
• chromosome testing (karyotype) and genetic panels or exome sequencing
• hormone tests: testosterone, LH, FSH, AMH and inhibin B, sometimes after stimulation with hCG
• imaging: pelvic ultrasound or MRI to look for a uterus and gonads
• laparoscopy and gonadal biopsy in some cases
• in adults with infertility: semen analysis and hormone tests

Management

• hormone replacement: testosterone or estrogen at puberty and beyond, depending on the person's gender
• surgery: orchiopexy to bring undescended testes into the scrotum, ideally by 18 months, and hypospadias repair when appropriate
• gonadal tumor risk management: removal of streak gonads in complete gonadal dysgenesis, and monitoring or removal in other forms depending on risk
• testicular self-examination and follow-up for those with retained testes, because of the increased testicular cancer risk
• fertility care: sperm banking and assisted reproduction. People with Swyer syndrome may carry a pregnancy using a donor egg
• psychological support for the person and family, and shared decision-making about any elective surgery

Frequently asked questions

What is testicular dysgenesis?

Testicular dysgenesis means the testes did not develop normally before birth. It ranges from complete gonadal dysgenesis, where gonads do not form testes at all, to milder forms linked with undescended testes, hypospadias, low sperm counts and testicular cancer.

What is testicular dysgenesis syndrome?

Testicular dysgenesis syndrome is a proposed concept linking undescended testes, hypospadias, poor semen quality and testicular cancer, suggesting they share a common origin in abnormal fetal testis development, possibly influenced by genes and environmental exposures.

What is Swyer syndrome?

Swyer syndrome, or complete 46,XY gonadal dysgenesis, is a condition in which a person has XY chromosomes but gonads that do not develop into testes. They have typical female genitals and a uterus, and need hormone therapy for puberty. The gonads are usually removed because of tumor risk.

Does testicular dysgenesis cause infertility?

It often affects fertility. Men with milder forms may have low sperm counts, and those with more significant dysgenesis may produce no sperm. Assisted reproduction, sperm retrieval or donor options can help many people build families.

Does testicular dysgenesis increase cancer risk?

Yes. Dysgenetic gonads, particularly those containing a Y chromosome, have a higher risk of germ cell tumors, including testicular cancer. Depending on the type, doctors recommend removing the gonads or regular monitoring and self-examination.