Testosterone is the most important androgen in men. It regulates a number of vital processes in the body and is responsible for the development and maintenance of secondary male characteristics.
When testosterone levels fall, patients can experience adverse physical and psychological effects and a subsequent reduction in quality of life.
Testosterone deficiency (TD) is defined as a clinical AND biochemical syndrome associated with advancing age and comorbidities characterised by a deficiency in serum testosterone PLUS relevant signs and symptoms.
Hypogonadism can either occur as a primary or secondary syndrome, depending on the aetiology and when it occurs in man’s lifetime:
- Primary hypogonadism usually presents before or around puberty in men and is usually due to testicular failure
- Congenital primary gonadal disease
- Acquired primary gonadal disease
- Secondary hypogonadism presents later on in a man’s life, most typically for men in their 40s and beyond. Reduced gonadotrophins occur most likely due to hypothalamic-pituitary dysfunction
- Age related (most common cause)
- Alcohol related (second most common cause)
- Congenital e.g. Kallman’s syndrome
- Secondary e.g. pituitary tumours
- Reversible secondary hypogonadism may be the result of systemic illness e.g. end-stage respiratory or renal disease, obesity, hyperprolactinaemia, long-term excessive exercise, poor nutritional status, high doses of steroids, medicinal drugs (spironolactone, ketoconazole, marijuana).
Transient Bone Marrow Oedema Syndromes
Bone marrow oedema syndromes encompase a group of conditions where bone swelling occurs causing pain and dysfunction.
They differ from more “traditional” stress injuries in that:
- They are diffuse and migratory in nature
- They are multifocal in origin (typical stress injuries usually have a single focus of stress)
- There is not always a clear cut aetiology or causal factor
Bone marrow syndromes usually manifest in a variety of clinical syndromes such as:
- Transient osteoporosis of the hip
- Bone marrow oedema syndrome of the foot and ankle
- Regional migratory osteoporosis
- Reflex sympathetic dystrophy
There is evidence that this phenomenon is associated with metabolic disturbances including:
- Vitamin D deficiency
- Hormonal disturbances (thyroid, growth hormone, testosterone, luteinising hormone and follicle stimulation hormone)
- Pregnant women especially during the third trimester
- Liver disease (e.g., cirrhosis)
- Type IV hyperlipoproteinemia
In this newsletter we present a case of bone marrow oedema syndrome of the foot and ankle caused by hypogonadism, its clinical presentation and management.
- 43-year old man presenting with right midfoot discomfort on running
- Started 6 months ago
- No swelling or bruising over forefoot/midfoot
- Runs 40-50 miles a week with a well considered running programme
- No recent changes in training volume or load
- No recent changes in footwear
- Good diet eating meat, diary and calorie intake
Previous treatment and investigation:
- Sent for x-ray by GP – normal bone structure
Past Medical history:
- BMI 23
- No history of ill health
- No family history of poor health or bone health
- No previous issues of pitutary deficieny or sex hormone characteristics
- Normal age of puberty
- Normal age to develop secondary sex characteristics
- Recreational club runner, preferred distance 10km (PB sub 45min)
- Good variation of training but now unable to run due mid foot pain
- Drinks 14-18 units week
- Non specifc vague tenderness across the right midfoot
- No left foot symptoms
- Good range of movement in ankles bilaterally
- No medial tibial pain or evidence of shin splints bilaterally
Clinical suspsicions, reasoning and differentials:
- Midfoot arthritis. Midfoot pain can be typically associated with arthritic changes, particularly in runners. Arthritic changes in the midfoot is usually associated with swelling, stiffness and redness.
- Cysts. Ganglia and cysts arising from the subtalar joint, sinus tarsi, intertarasal and metatarsal joints are very common. Aspirating them can bring patients a relief of “pressure” and pain in the midfoot.
- Ligamentous sprain. No clear history of sprain or fall makes a midfoot ligamentous injury (e.g., lisfranc, tarsometatarsal) unlikely. But ligamentous structures in the midfoot can also be underchronic stress
- Tendinitis. The most common extensor tendons to become inflammed in the midfoot are extensor digitorum and extensor hallucis longus. This often presents with crepitus, swelling and pain.
- Bone stress. Isolated bone stress phenomena in the midfoot is also very common. The more commonly affected bones include the navicular and cuboid in the medial arch and the base of 2-4th metatarsal.
MRI scanning shows widespread bone stress patterns across the midfoot, subtalar joint and calcaneum (as shown by multiple foci of high signal on T2 weighted images).
Blood tests reveal low testosterone and vitamin D profiles (abnormal results highlighted with normal ranges in brackets):
- Calcium and ALP normal
- Thyroid profile normal
- Liver profile, boderine abnormal
- Vitamin D 40 nmol/L, low (< 25 Deficient, 25-50 Insufficient)
- Serum Testosterone, low 10 ( 8.64-29.0) nmol/L
- Sex Hormane Binging Globulin, low, 20 ( 18.3-54.1 ) nmol/L
- Free Androgen Index 14, deficient ( 22-104 ) nmol/L
- DEXA scan confirms normal bone density in the lumbar spine and hip
Diagnosis & Management
This patient had Transient Bone Oedema Syndrome of the foot and ankle due to secondary hypogonadism (aka hypogondotrophic hypogonadism) due to age and alcohol consumption. This diagnosis was made from combining his:
- Clinical symptoms
- Musculoskeletal injury pattern
- Abnormal liver blood tests
- Abnormal sex hormone profile
This patient was started on testosterone therapy to treat his hypogonadism. Serial DEXA and MRI scans after 1 year showed improvement in the Transient Bone Marrow Oedema in the foot. Appropriate load and running adjustment was made whilst he was being replaced. Within one year, he was back to full running and training.
Discussion and clinical considerations
Bone marrow oedema syndrome of the foot and ankle is the most common of the bone marrow syndromes. They usually diffuse bone stress across the midfoot bones and in this case the heel and calcaneum. Symptom presentation for this bone stress syndrome is very vague with feelings of pain and stiffness in the midfoot.
When detected in patients both male and female further biomechanical and metabolic assessment must be conducted. This includes:
- Full biomechanical and sports podiatric review to assess foot posture and gait/running analysis
- Training volume and loading strategies to be discussed
- Blood tests to look for metabolic and hormonal deficienies
- DEXA scanning to investigate bone density
- Further bone turnover and metabolism tests if required (e.g., urinary calcium)
This patient had low Serum Testosterone, SHBG and free Androgen likely contributing to his symptoms. This is most likely to be an age related phenomena but could also be influenced by the patient’s alcohol consumption.
Key clinical history points in a male patient with suspected hypogonadism include:
- Age of puberty (if suspecting primary hypogonadism)
- Age of developing of male secondary sexual characteristics (pubic hair, facial hair, voice depends)
- Development of female sexual characteristics (breast development, high pitch voice, hairlessness)
- Other signs of pituitary dynsfuction (sexual development, thyroid function, growth, skin pigmentation and adrenal function). This is most commonly caused by a benign pituitary tumour which can cause visual symptoms (typically bilateral hemianopia). Signs of secondary hypogonadism including:
- Decreased libido (sex drive)
- Erection problems
- Weight gain
- Night sweats
- Short term memory loss
- Musculoskeletal injury
If suspected blood tests can be revealing. In men total testosterone levels decline with age, falling by about 1% a year after the age of 30. Normal ranges for a male of 70 will be different to a 30 year old. However, standard laboratory ranges do not reflect this so it is important to consider this when evaluating results.
The graph below shows the decline of the common sex hormones in men and women.
The green line shows decline in growth hormone in men and women.
The purple line shows decline of oestradiol in women.
The blue line shows the decline of testosterone in men.
It is important to note that the decline of testosterone in men is slow and progressive and no way near as dramatic as the peri/post menopausal drop of oestrogen in women. The “manopause” is perhaps therefore a slightly overstated phenomena. Having said that, the highest prevalance of male secondary gonadism is in men beyond the age of 40 so does need to be considered.
From a blood profiling point of view, while total testosterone is the most frequently quoted measure, most testosterone in the blood is not actually available for use by the body. Around 40-50% is weakly bound to a type of protein called albumin and 50-60% is tightly bound to Sex Hormone Binding Globulin (SHBG), a protein produced by the liver. This means only 1-3% is left circulating as free testosterone. It is important to evaluate all hormone profiles including the pitutary access when assessing for testosterone deficiency.
Management considerations of secondary hypogonadism with TRT
The management of secondary hypogonadism usually requires testosterone replacment therapy (TRT) and ongoing monitoring.
Musculoskeletal injury particularly bone stress issues is now recognised as a primary reason to start testosterone in men who are deficient (similarly to oestrogen in women with MSK injury).
While some studies have raised concerns about the impact of TRT on a man’s risk of heart attacks or on their heart and circulation more generally, an in-depth review of research by the European Medicines Agency did not find any conclusive evidence that these were valid.
Similarly, despite concerns first raised in the 1940s about TRT and prostate cancer, a review of research by the British Society of Sexual Medicine has found no compelling evidence of any link between the two. However, every effort should be made to exclude pre-existing prostatic cancer by clinical examination and a sensitive blood test to measure the levels of Prostate Specific Antigen (PSA) in advance of any course of testosterone replacement therapy.
To ensure the safety and effectiveness of treatment, including giving the right dosage, it is essential that the results of treatment are carefully monitored, both to establish the diagnosis and to monitor the treatment carefully, blood tests and laboratory measurements are required at regular intervals. After the initial consultation and diagnosis, detailed clinical examinations need to be carried out at 3-6 month intervals.
Testosterone replacement therapy (TRT) is usually it’s given by testosterone gel or injections depending on patient preferrence. For the first two to six months a testosterone gel is usually recommended. This method can safely be continued for as long as you are happy with the daily applications. In the long term, some patients prefer the ease of long acting injections which are given six to 10 weeks apart. Another form of treatment is to boost the body’s own production of testosterone by using medications including Clomid (Clomiphene Citrate).
The flow chart from British Society of sexual medicine gives a detailed over view of an evidenced based treatment alorhythm for secondary hypogonadism.
It is vital to make sure the patient fully understands the risks and benefits before starting testosterone replacement and should be prescribed by an appropriately trained clinician practitioner.
Adapted from Minhas and Mulhall, 2017.1 Copyright © British Society for Sexual Medicine. December 2017.
TT – total testosterone, LH – luteinizing hormone, FSH – follicle stimulating hormone, SHBG – sex-hormonebinding globulin, FT – free testosterone, CV – cardiovascular, CVD – cardiovascular disease, T Therapy -testosterone therapy, HCG -human chorionic gonadotropin, SERMs – selective oestrogen receptor modulators, AIs – aromatase inhibitors, PSA – prostate specific antigen,
*For men with TT levels <5.2nmol/L plus low LH and FSH or increased prolactin levels, refer to endocrinology or arrange a pituitary MRI to exclude a pituitary adenoma3,6
**These drugs should not be used if pituitary function is compromised. SERMs and aromatase inhibitors are not currently licensed for TD
Key Summary and learning points
- Transient Bone Marrow oedema of the foot and ankle is the most common presentation of this syndrome
- Suspect hypogonadism in male patients with this condition
- Primary hypogonadism will often be picked up in childhood/adolescent years
- History taking, examination and blood profiling is required to make the diagnosis of secondary hypogonadism
- Age and excessive alcohol consumption are the main causes of secondary hypogonadism (however, there are other medical causes that need to be considered)
- The physiological drop in testosterone in not as rapid in middle aged men as it is for oestrogen in women
- Treatment of secondary hypogonadism usually involves Testosterone Replacement Therapy (TRT)
- Patients should receive proper counselling on TRT before starting with regular follow ups