XX Gonadal Dysgenesis: Females Without Ovaries

What Is XX Gonadal Dysgenesis?

46, XX gonadal dysgenesis is a primary gonadal ovarian defect leading to premature failure in the development of ovaries in otherwise normal females. It may occur due to failure in the developmental process of gonads or due to resistance to gonadotropin hormone stimulation. It is an autosomal disease and is called pure gonadal dysgenesis.

What Is Gonadal Dysgenesis?

Gonadal dysgenesis is defined as any congenital (since birth) developmental disorder of the male or female reproductive system. It is characterized by a subsequent loss of germ cells of the developing gonads in an embryo. This progressive loss of germ cells can lead to underdeveloped gonads, known as streak gonads, that are extremely dysfunctional. Genotypes showing complete gonadal dysgenesis are either 46, XX, or 46, XY.

Streak Gonads: Gonads that are extremely hypoplastic, dysfunctional, and comprise mainly fibrous tissue are known as streak gonads.

How Is Pure Gonadal Dysgenesis Different From Turner Syndrome?

• Pure gonadal dysgenesis is used to differentiate a group of affected individuals from gonadal dysgenesis linked to Turner syndrome.

• Turner syndrome is a distinct chromosomal disorder with a missing or incomplete X chromosome.

• Whereas in pure gonadal dysgenesis, the chromosomal gene constitution is either 46, XX or 46, XY. Pure gonadal dysgenesis is often characterized by primary amenorrhoea with or without developing secondary sex characteristics.

How Does XX Gonadal Dysgenesis Differ From XY Gonadal Dysgenesis?

• Complete gonadal dysgenesis genotypes can be either 46, XX, or 46, XY. These patients usually present with streak gonads, female external genitalia, amenorrhea, and a significant lack of female secondary sexual characteristics.

• The 46, XX type of gonadal dysgenesis usually develops due to mutations in the chromosomal genes or alterations in the environmental factors leading to impaired ovarian development, thereby resulting in ineffective and dysfunctional ovaries. 46, XX type gonadal dysgenesis causes premature ovarian failure in the affected females.

• The 46, XY type of complete gonadal dysgenesis usually develops due to genetic mutations in the sex-determining region (SRY) of the Y chromosome. The SRY gene that occurs on the Y chromosome is the main essential switch responsible for turning on the processes of testicular development. XY gonadal dysgenesis is also referred to as Swyer syndrome.

What Is the Molecular Pathogenesis of XX Gonadal Dysgenesis?

• XX gonadal dysgenesis is a hereditary, autosomal recessive disorder. However, this type of gonadal dysgenesis's exact pathogenesis is unclear.

• Inactivating genetic mutations in the FSHR gene coding for the follicle-stimulating hormone receptor have been linked to 46, XX dysgenesis.

• Genetic mutation in this receptor thereby leads to blockage in the development of follicles. This, in turn, allows the follicle to remain in the primary stage.

• Additional studies have also reported the role of the gene BMP15 (bone morphogenetic protein 15) in the pathogenesis of XX gonadal dysgenesis. However, a definite link to gonadal dysgenesis is not yet established. BMP15 (bone morphogenetic protein 15) is a gene that helps in protein-coding.

What Is the Pathophysiology Of XX Gonadal Dysgenesis Disorder?

Premature failure of the development of ovarian follicles results in their depletion, thereby resulting in impaired estrogen secretion and the loss of development of secondary sexual characteristics in the affected females.

It is a very rare congenital disorder. The prevalence of the disease is unknown but is approximately less than 1/10,000.

What Are the Symptoms of XX Gonadal Dysgenesis Disorder?

46, XX Gonadal dysgenesis is a rare genetic disorder associated with the following:

• Delayed puberty.

• Primary amenorrhea (absence of menstrual cycle).

• Premature menopause.

• Hypogonadotropic hypogonadism (a condition defined as a deficiency of gonadal hormone secretion that is compensated by a rise in the secretory levels of pituitary gonadotropin hormones).

• Uterine hypoplasia (when a female is born with a congenitally smaller uterus).

• The female with streak gonads.

• The female with normal height.

• The internal and external genitalia are developed in a normal manner.

• Deafness with or without cerebellar ataxia, known as Perrault syndrome, may also be seen in a few cases.

• Intellectual disability.

• Peripheral neuropathy.

• Infertility.

• Normal breast development is absent.

• Widening of hips and pelvis is also absent.

What Are the Diagnostic Methods For XX Gonadal Dysgenesis Disorder?

Diagnosis of the disorder requires:

1. Hormone Evaluation- Evaluation of the hormones (both gonadal and adrenal) should be done.

• Serum Estrogen and Progesterone Levels- Due to the lack offunctional ovaries, serum estrogen and progesterone levels are decreased.

• Serum Follicle Stimulating Hormone and Luteinizing Hormone- High levels of serum follicle-stimulating hormone and luteinizing hormone are also observed, indicating that the pituitary gland is providing the signal for the attainment of puberty, but the gonads fail to respond.

2. Karyotype Analysis- Analysis of the person’s karyotype (an image produced of the patient’s chromosomes derived from a single unit of the cell) can be done in a laboratory. The karyotype checking reveals the presence of XX chromosomes.

3. Pelvis Imaging- Imaging of the pelvis can also be done. The imaging demonstrates the absence of ovaries with the presence of a uterus. The streak gonads are usually not visible in most imaging techniques.

4. Laparoscopy- In some cases, laparoscopy is also required, along with the biopsy of the ovarian tissue.

5. Biopsy of Gonads- Microscopic examination reveals subsequent loss of the germ cells in the developing gonads of the fetus. This, in turn, leads to extremely hypoplastic ovaries that are mainly composed of fibrous tissue. These defective ovaries are known as streak gonads.

6. Genetic Counseling- Counseling should be offered to the affected individual regarding the genetic disorder mentioning their medical condition.

What Is the Treatment of XX Gonadal Dysgenesis?

The treatment of the disorder requires estrogen and progesterone hormone administration therapy. The consequences of the female patient suffering from this syndrome are:

• The inability of the gonads to synthesize estrogen. Therefore, the breasts will fail to develop, and the uterus will not show any growth. There will be no menstruation until hormone replacement therapy is given. Estrogen is often administered through the cutaneous site.

• Menstrual periods will not be regularized because the gonads fail to produce progesterone. A pill called Progestin is usually given in such cases.

• The inability of the gonads to produce eggs. Embryo transfer can be done in such cases by the implantation of the fertilized egg of another woman.

• Additional supplements like calcium and vitamin D may also be suggested.

Conclusion

XX gonadal dysgenesis is a congenital, rare autosomal disease characterized by a defect in the development of gonadal ovaries, thereby leading to a lack of appearance of secondary sexual characteristics. An early diagnosis is therefore extremely essential to promptly diagnose the disorder to begin treatment for the control of symptoms and reduce the risks related to this disorder. Patients and their families should also be offered psychological support and their families.