Hypogonadism

Hypogonadism is a syndrome associated with impaired function of the gonads. The term “gonads” refers to the testicles and ovaries - the organs that produce gametes (sperm and ova) and sex hormones (testosterone, dihydrotestosterone, oestrogen and progesterone).

🏃‍♀️ Physiology

The hypothalamic-pituitary-gonadal axis (HPG axis) is the endocrine axis that is involved with development, reproduction and aging.

1. As with most endocrine axes, it starts in the hypothalamus. The infundibular nucleus of the hypothalamus produces Gonadotropin-releasing hormone (GnRH).
2. GnRH is released into the hypophyseal portal system in 2 distinct manners: pulsatile and surge. The pulsatile release refers to secretion refers to episodic secretion of GnRH. The surge release specifically occurs during the pre-ovulatory phase in females and in this phase secretion is persistent. The GnRH travels through the portal system to the anterior pituitary.
3. Gonadotropic cells in the anterior pituitary have GnRH receptors on their membrane. When stimulated by GnRH, these cells produce and secrete luteinising hormone (LH) and follicle stimulating hormone (FSH) into the body.
4. In men - LH stimulates Leydig cells to convert cholesterol into testosterone. This testosterone, along with FSH, stimulates Sertoli cells within the seminiferous tubules to produce sperm (spermatogenesis).

4. In women - FSH stimulates the development of ovarian follicles. One, sometimes two, follicles become the dominant follicle. This follicle releases oestrogen which suppresses FSH and GnRH during the follicular phase. LH levels gradually increase as the ovaries mature. Mid-cycle, 24-36 hour before ovulation, LH levels surge. It is this surge that triggers the release of the mature egg from the dominant follicle. LH then supports the corpus luteum after ovulation during the luteal phase.
5. Testosterone inhibits GnRH and LH, while inhibin (released by Sertoli cells) inhibits FSH. Oestrogen also inhibits GnRH in females while the granulosa cells also produce inhibin to limit FSH production.

🔢 Classification and pathophysiology

• Primary hypogonadism

Also known as hypergonadotropic hypogonadism. In this instance the issue lies with the gonads themselves and not the hypothalamus or pituitary. As such the hypothalamus produces GnRH, LH and FSH as per usual. However, the gonads are unresponsive to the LH and FSH and as such the sex steroids are not produced (hypogonadism). Furthermore there is a lack of negative feedback which means the hypothalamus and gonadotropic cells continue to produce GnRH, FSH, LH (hence “hypergonadotropic”).

Instances in which primary hypogonadism is seen are:

1. Congenital anomalies - such as Turner syndrome (46 XO) and Klinefelter syndrome (47 XXY).
2. Acquired gonadal injury - this may occur with surgery, chemotherapy, radiotherapy, autoimmune disease, infection or trauma that affects the gonads.

• Secondary hypogonadism

This is known as hypogonoadotropic hypogonadism. As the name implies there reduced function of the gonadotropic cells. The impairment may be at a hypothalamic or pituitary level, meaning there is reduced release of GnRH or LH and FSH.

Instances in which secondary hypogonadism is seen are:

1. Hypothalamic or pituitary tumours (such as craniopharyngioma, pituitary adenomas)
2. Kallmann syndrome - a condition characterised by delayed/absent puberty (hypogonadism) and impaired smell (hyposmia or anosmia).
3. Prader-Willi syndrome - a genetic condition on chromosome 15 that leads to short stature, excessive hunger, hypotonia, hypogonadism, learning difficulties and behaviour difficulties.
4. Gaucher disease - a metabolic disorder relating to lipid storage.
5. Idiopathic hypogonadotropic hypogonadism (IHH)
6. Excessive exercise or malnutrition - these may cause hypothalamic amenorrhoea.
7. Opioid use - opioids inhibit pulsatile secretion of GnRH.
8. Acquired hypothalamic/pituitary injury - once again due to similar factors as mentioned above.

😷 Presentation

Hypogonadism in males:

• Delayed puberty
• Microorchidism (small testes)
• Absent/reduced terminal and pubic hair - vellus hair usually changes to terminal hair in the presence of androgens. Hair will now grow in the pubic region, armpits and face.
• High-pitched voice
• Smooth skin - with an absence of acne.
• Lowered lean body mass - males tend to gain muscle mass in puberty.
• Genital abnormalities - such as undescended testes or hypospadias.
• Weight gain

Hypogonadism in females:

• Delayed puberty
• Primary amenorrhoea
• Secondary amenorrhoea
• Vaginal dryness & other postmenopausal symptoms

Symptoms that are seen in both males and females include:

• Weight gain
• Osteoporosis - testosterone and oestrogen promote osteoblast activity and reduces osteoclast activity.
• Infertility and low libido
• Fatigue
• Depression

The patient should also be assessed for features of other conditions:

1. Klinefelter syndrome - gynaecomastia in men.
2. Turner syndrome - webbed neck and short stature in women.
3. Kallmann syndrome - anosmia, absent breast development, syndactyly, cleft lip/palate.
4. Gaucher disease - hepatomegaly, splenomegaly, bone pain.

🔍 Investigations

• Bloods - such as FBC, U&Es, LFTs, TFTs.
• Serum testosterone in males - <300ng/dL.
• Serum oestrogen in females - typically low.
• GnRH, LH and FSH - this helps differentiate between primary and secondary hypogonadism:

	GnRH	LH	FSH
Primary hypogonadism	High	Low	Low
Secondary hypogonadism	Low	Low	Low

• DEXA scan - reduced bone mineral density.
• Genetic testing
• MRI of the brain

🧰 Management