Gonadotropin insensitivity

Overview

Gonadotropin insensitivity, also known as gonadotropin resistance, is a rare endocrine disorder in which the body's gonads (testes in males or ovaries in females) do not respond properly to the pituitary hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones are essential for normal sexual development and reproductive function. In individuals with this condition, despite normal or elevated levels of LH and FSH, the gonads fail to produce adequate levels of sex hormones (testosterone or estrogen) or function normally, leading to disorders of sexual development and infertility.

Causes

Gonadotropin insensitivity is typically caused by genetic mutations that affect the receptors for LH or FSH on gonadal cells. These include:

• FSH receptor (FSHR) gene mutations: Lead to resistance to FSH, affecting ovarian follicle development in females or spermatogenesis in males

• LH receptor (LHCGR) gene mutations: Lead to Leydig cell hypoplasia in males, impairing testosterone production

The condition is usually inherited in an autosomal recessive pattern, meaning both copies of the relevant gene must be mutated for the disorder to manifest. It can present in both males and females but often with different clinical features.

Symptoms

The symptoms of gonadotropin insensitivity depend on the specific receptor affected and the severity of the resistance. Common features include:

In Females:

• Primary amenorrhea (absence of menstruation)

• Delayed or absent puberty

• Infertility

• Small or underdeveloped ovaries

In Males:

• Undescended testes (cryptorchidism)

• Ambiguous genitalia or undervirilization in severe cases

• Delayed puberty

• Infertility due to lack of sperm production

• Low testosterone despite high LH levels (in LH receptor mutations)

Diagnosis

Diagnosis of gonadotropin insensitivity involves clinical evaluation, hormonal profiling, imaging studies, and genetic testing:

• Hormonal assays: High or normal levels of LH and FSH with low sex steroid levels (testosterone or estrogen)

• Pelvic or scrotal ultrasound: To assess gonadal structure

• MRI of the pituitary: To rule out central causes of hypogonadism

• Karyotyping: To evaluate chromosomal sex and rule out other disorders of sex development

• Genetic testing: To confirm mutations in FSHR or LHCGR genes

Treatment

Treatment of gonadotropin insensitivity focuses on hormone replacement and management of reproductive issues. Specific interventions include:

For Females:

• Estrogen replacement therapy: To induce and maintain secondary sexual characteristics and menstrual cycles

• Progesterone: Added cyclically to protect the uterine lining if the uterus is present

• Assisted reproductive technologies (ART): May be considered for fertility options, although success is limited in severe resistance

For Males:

• Testosterone replacement therapy: To induce puberty, promote virilization, and maintain male characteristics

• Surgical correction: For undescended testes or genital anomalies if present

• Sperm retrieval and ART: May be attempted in cases with partial receptor function

Prognosis

The long-term prognosis of gonadotropin insensitivity varies based on severity and timely diagnosis. With appropriate hormone replacement therapy, most individuals can achieve normal secondary sexual development and maintain general health. However, fertility is often impaired, particularly in severe cases, and may not be correctable with current technologies. Lifelong endocrinological monitoring is typically required. Psychological support and genetic counseling are also important aspects of care, especially for patients and families coping with reproductive challenges and disorders of sex development.