11th April 2024

Hypogonadism

Physiology

The normal functioning of the Hypothalamic-Pituitary-Adrenal axis (HPA axis) consists of a series of negative feedback loops that regulate the release of hormones from endocrine glands around the body. The HPA regulation of reproductive hormone release involves the secretion of GnRH from the hypothalamus. GnRH acts on anterior pituitary gonadotrophs to release LH and FSH. LH and FSH then act on cells in the gonads to produce sex hormones, predominantly testosterone in males and oestrogen in females. Testosterone and oestrogen have an inhibitory effect on the release of GnRH from the hypothalamus and FSH and LH from the Anterior Pituitary.

Pathophysiology

Defined as failure of the gonads to produce adequate sex hormones, hypogonadism can be classified by aetiology into primary (gonadal) or secondary (central/extra-gonadal). Primary hypogonadism results from pathology of the sex glands, while secondary hypogonadism is caused by disruption of the HPA axis. In females, this results in ovarian dysfunction with a degree of impaired oestrogen production and ovulatory failure.

Aetiology

Primary hypogonadism

Primary hypogonadism (hypergonadotropic hypogonadism) in a woman is a pathology of the ovaries resulting in failure of normal ovulation and production of adequate oestrogen. It is characterised by disruption to the menstrual cycle (amenorrhoea/oligomenorrhoea) as well as biochemical features such as raised FSH and LH with low oestradiol. Congenital causes of gonadal dysgenesis include Turner (45X) and Fragile X syndrome. Streak ovaries are seen when there is abnormality or absence of the X chromosome and are associated with Turner syndrome. Acquired primary hypogonadism can be due to iatrogenic causes such as chemotherapeutic agents, therapeutic oophorectomy, as well as infections and autoimmune diseases, including haemochromatosis. 

Secondary hypogonadism

Secondary hypogonadism is caused by pathology of the HPA axis (hypothalamus and/or pituitary), resulting in a downstream reduction in the production of gonadotrophins. Congenital causes include Kallmann syndrome, which is the most common genetic cause and is seen more often in men (3.6:1). Space occupying lesions, infiltrative diseases such as sarcoidosis and amyloidosis, meningitis, pituitary apoplexy and Sheehan’s syndrome are examples of secondary causes.

Clinical Features

In pre-pubertal females, primary hypogonadism is more common and diagnosed at the time of expected puberty with primary amenorrhoea and a lack of secondary sexual characteristics. In post-pubertal females’ secondary hypogonadism is more common, and women present with secondary amenorrhoea/oligomenorrhoea as well as features of oestrogen deficiency.

Investigations

In women presenting with menstrual disturbance, clinicians should enquire about symptoms of oestrogen deficiency and other systemic features. 

Initial biochemical tests include human chorionic gonadotrophin (hCG) and FSH. LH, Oestradiol, testosterone, prolactin, thyroid stimulating hormone, and other pituitary function tests may be useful in aiding diagnosis.

In pre-pubertal females, screening for genetic causes of primary hypogonadism should be considered, such as a pelvic ultrasound scan and karyotyping if the uterus is absent.

Additional imaging, such as an MRI brain for patients with hypogonadotropic hypogonadism, may be considered if an intracranial cause is suspected based on clinical presentation. Abdominal imaging may reveal a local cause or horseshoe kidneys, which are associated with Turner syndrome.

Management

Hormone replacement therapy is the mainstay of treatment for hypogonadism. Treatment should be individualised to the patient, specific to the underlying aetiology and should take a holistic approach with consideration of psychosocial implications. As well as the physiological development of secondary sexual characteristics and fertility if desired, the main aim for treatment is to prevent long-term complications of low oestrogen, such as cardiovascular disease and osteoporosis. 

References

Dzemaili S, Tiemensma J, Quinton R, et al. Beyond hormone replacement: Quality of life in women with congenital hypogonadotropic hypogonadism. Endocrine Connections 2017; 6: 404–412.