Hypogonadism in females

What is hypogonadism in females?

Hypogonadism in females describes the inadequate function of the ovaries, with impaired production of germ cells (eggs) and sex hormones (oestrogen and progesterone).

• Primary hypogonadism refers to a condition of the ovaries (primary ovarian insufficiency/hypergonadotropic hypogonadism).
• Secondary hypogonadism refers to the failure of the hypothalamus or pituitary gland (hypogonadotropic hypogonadism).

What causes hypogonadism in females?

Hypogonadism in females is due to disruption of any section of the hypothalamic–pituitary–ovarian axis pathway (figure 1). In a correctly functioning hypothalamic–pituitary–ovarian axis pathway:

• The hypothalamus produces gonadotrophin-releasing hormone (GnRH) at the onset of puberty
• GnRH then acts on the pituitary gland, which produce follicle-stimulating hormone (FSH) and luteinising hormone (LH)
• FSH and LH then act on the ovaries to stimulate the production of oestrogen and progesterone.

The hypothalamic–pituitary–gonadal axis pathway in females 

Who gets hypogonadism?

Primary ovarian insufficiency and secondary hypogonadism may be congenital or acquired [1,2].

Congenital primary ovarian insufficiency

The main mechanism for congenital primary ovarian deficiency remains unknown in the majority of cases. Some cases relate to:

• Chromosomal abnormalities, such as Turner syndrome (45,X karyotype), fragile X syndrome, and galactosaemia (inability to process the sugar galactose)
• Ovarian dysgenesis (abnormal organ development) and agenesis (inability of the organ to develop during embryonic development)
• Congenital adrenal hyperplasia (17α-hydroxylase deficiency).

Acquired primary ovarian insufficiency

The causes of acquired primary ovarian insufficiency include:

• Medications, such as chlorambucil, cyclophosphamide, and alkylating agents
• Radiotherapy
• Autoimmune diseases including autoimmune polyglandular syndrome type 1
• Viral infections, including mumps oophoritis, tuberculosis (TB), malaria, varicella, and
• Bacterial infections, such as Shigella
• Iatrogenic disease, such as problems post-oophorectomy (surgical removal of the ovaries).

Congenital secondary hypogonadism

Congenital secondary hypogonadism is gonadotrophin deficiency due to a genetic mutation, such as in Kallmann syndrome.

Acquired secondary hypogonadism

Acquired secondary hypogonadism can be due to damage to the pituitary/hypothalamus. Causes of acquired secondary hypogonadism can include:

• Intracranial space-occupying lesions (eg, tumours and cysts)
• Infiltrative disease (eg, sarcoidosis and haemochromatosis)
• Infection (eg, meningitis and TB)
• Pituitary apoplexy (bleeding into pituitary gland)
• Trauma.

Gonadotropins can be suppressed by:

• Chronic disease (eg, diabetes, anorexia, obesity, and renal disease)
• Excessive exercise
• Critical illness
• Chronic opiate, glucocorticoid, or anabolic steroid use
• Hyperprolactinaemia (an excess of the milk-inducing hormone prolactin).

What are the clinical features of hypogonadism in females?

The clinical features of hypogonadism depend on the age at presentation [3].

Oestrogen deficiency pre-puberty

Symptoms of low oestrogen levels are rarely present in hypogonadism pre-puberty. The presenting features are absent pubertal development (reduced growth and absence of pubic hair) and primary amenorrhoea (absence of menarche).

Oestrogen deficiency after completion of puberty

After the completion of puberty, the features of hypogonadism include:

• Secondary amenorrhoea (cessation of regular menses for 3 months or the cessation of irregular menses for 6 months)
• Symptoms of the climacteric (peri-menopause): palpitations, heat intolerance, flushing, night sweats, irritability, anxiety, depression, sleep disturbance, loss of libido, coarse hair, vaginal dryness, and fatigue
• Infertility.

What are the complications of oestrogen deficiency?

The long-term risks of oestrogen deficiency include an increased risk of osteoporosis and cardiovascular disease. The risk is greater with a younger age of onset. In contrast, the risk of breast cancer may be slightly reduced.

What skin changes may be due to hypogonadism in females?

Oestrogen has a key role in maintaining skin health. Oestrogen helps maintain skin thickness and collagen levels, skin elasticity, and moisture. It is also thought to play a role in wound healing [4].

Low oestrogen levels are associated with:

• Dry, thin skin
• Potentially increased wrinkles
• Delayed wound healing
• Loss of elasticity, thickness, and moisture of vulval skin, resulting in genitourinary discomfort.

Skin changes may also reflect the underlying cause of hypogonadism; for example, hyperpigmentation may be a sign of an autoimmune disease.

How is hypogonadism diagnosed?

If hypogonadism is suspected following a detailed history and examination, the following investigation pathway can be followed.

• The patient should be referred to a specialist.
• Initial investigations should include [5,6]:
  • Human chorionic gonadotropin (hCG) exclude pregnancy
  • FSH and LH
  • Oestradiol
  • Thyroid-stimulating hormone (TSH) — thyroid disorders can present with amenorrhoea
  • Serum prolactin
  • Pelvic ultrasound scan — pre-puberty.

Interpretation of results

• A positive hCG test is due to pregnancy.
• If the uterus is absent or there are other anatomical anomalies, a karyotype test should be performed.
• Low or low/normal FSH and LH levels may indicate hypogonadotropic hypogonadism. An MRI brain should be considered.
• Pre-puberty, high FSH and LH levels may indicate primary ovarian insufficiency. Adrenal hormones should be assessed and a karyotype test should be performed.
• A raised prolactin result should prompt consideration of a pituitary MRI.

What is the treatment for hypogonadism in females?

Treatment of hypogonadism is directed at the underlying pathology where possible, helping the woman become fertile if desired, and preventing the long-term complications of hypoestrogenism (ie, osteoporosis, increased cardiovascular disease, and urogenital atrophy).

As a general rule, women of reproductive age with hypoestrogenism should receive hormone replacement therapy. Specialist input should be sought, as there are potential significant complications of hormone therapy, such as:

• Endometrial hyperplasia and carcinoma in unopposed oestrogen therapy — it is usual to add a progestin to stop this
• Increased risk of breast cancer, venous thromboembolism, stroke, and ischaemic heart disease.

Post-menopause, hormone replacement therapy is indicated for significant symptoms.