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Bone Stress and Hypogonadism

Male Hypogonadism

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. 

Case Presentation

Clinical history:

  • 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

Exercise history:

  • Recreational club runner, preferred distance 10km (PB sub 45min)
  • Good variation of training but now unable to run due mid foot pain

Social history:

  • Accountant
  • Drinks 14-18 units week

Clinical examination:

  • 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:

  1. 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. 
  2. 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. 
  3. 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 
  4. 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. 
  5. 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

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). 

Other Investigations:

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
    • Fatigue
    • Depression
    • Weight gain
    • Night sweats
    • Short term memory loss
    • Irritability
    • Infertility
    • 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.

Screenshot 2023 12 13 at 08.57.50 Bone Stress and Hypogonadism

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.

Screenshot 2023 12 13 at 08.58.27 Bone Stress and Hypogonadism

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
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    Orla Mulligan
    Administration and Social Media Manager
    Administration, LBSM

    Orla Mulligan is the administration and social media manager for LBSM. She has a strong background in sport having herself played netball at an elite standard for the U21s Northern Ireland team in the European Championships as well as the U21s competition for Saracen Mavericks.

    She understands youth sport pathways having herself played and training in the netball Kent regional pathway. She has a keen interest in most sports and a good understanding of how injury and illness can impact on the mind and body, as well as rehabilitation pathways.

    She looks forward to speaking and assisting LBSM patients and gives her best support to them during their treatment pathway.

    A day in the life of Orla involves communicating with patients via phone and email, managing and organising clinics, operations and media management.

    Outside of work, Orla is a gym enthusiast, enjoys tennis and still finds the time for an occasional game of netball.

    Maddie Tait
    BSc, MSc
    Associate, LBSM
    Musculoskeletal and Sports Podiatrist

    Maddie treats and manages complex foot and ankle injuries in London and Surrey.

    She is particularly interested in helping her patients improve their quality of life and achieve their personal goals, working closely with Foot and Ankle Consultants, Sports Medicine Doctors and Physiotherapists.

    Maddie has a sporting background herself having previously represented England in Hockey. She understands the demands of elite sport and the importance of physical and mental health. In her spare time, Maddie continues to enjoy an active lifestyle by running, cycling and attending a Pilates class.

    Having graduated from University of Brighton with a MSc (hons) in Podiatry, Maddie focused her career in Podiatric Sports Injuries and Biomechanics. Previously she completed a BSc (hons) in Sport Science at Loughborough University.

    A day in the life of Maddie involves consulting patients in clinic, performing gait and biomechanical assessments, measuring and fitting orthotics and braces. She also regularly teaches and presents at sports medicine and podiatry conferences.

    Outside of work, Maddie still finds time to play hockey and enjoys running and skiing.

    Mr Prakash Saha
    MBBS, PhD, FRCS
    Consultant Partner, LBSM
    Consultant in Vascular Surgery

    Mr Prakash Saha is a Consultant Vascular Surgeon at LBSM. He takes pride in providing the best possible results for his patients by using the most appropriate non-surgical and surgical methods based on clinical evidence, patient results and satisfaction.

    He treats fit and active people suffering with a range of cardiovascular issues, from painful leg swelling associated with exercise to venous insufficiency, post-thrombotic syndrome and leg ulcers. He also treats people with arterial system problems including poor circulation, compression syndromes and aneurysms. He carries out both endovascular and open aortic repair and has some of the best outcomes in the country.

    Mr Saha studied medicine at the United Medical & Dental Schools at Guy’s and St. Thomas’ Hospitals before completing his higher surgical training in London and the South East. During this time, he was awarded the prestigious NIHR Clinical Lectureship in Vascular Surgery at St. Thomas’ Hospital, giving him comprehensive training in open and endovascular techniques for treating arterial and venous disease. Prakash completed his aortic surgery training at the St. George’s Vascular Institute before carrying out a specialist fellowship at the Royal Prince Alfred Hospital, Sydney.

    Mr Saha regularly lectures and runs workshops across the globe on the latest surgical techniques to treat vascular disease. He has also been awarded a number of research grants from the Royal College of Surgeons, the Circulation Foundation, the Wellcome Trust, the Academy of Medical Sciences, and the British Heart Foundation, which has led to over 80 publications and the development of innovative technologies to help treat patients. For this work, Prakash has received a number of prizes, including the Venous Forum prize from the Vascular Society of Great Britain and Ireland, an International Young Investigator Award, and an Early Career Investigator Award from the American Heart Association.

    A day in the life of Mr Saha involves seeing patients in clinic, operating in surgical theatre or lecturing at his university. He also regularly teaches and presents at vascular and sports medicine conferences.

    Mr Saha is an avid cyclist and tennis player (although yet to get a set of Dr Seth!). Outside of work, he spends time with his family who consists of 3 children and enjoys travelling.

    Dr Gajan Rajeswaran
    MBBS, FRCR
    Consultant Partner, LBSM
    Consultant in Sports and Musculoskeletal Radiology

    Dr Gajan Rajeswaran is a Consultant Musculoskeletal Radiologist at LBSM, with an extensive background of working in elite sport. He is one of the most recognised radiologists in the sports medicine field. He provides top level imaging and medical diagnostic services for patients and athletes.

    Dr Gajan Rajeswaran completed his undergraduate medical training at Imperial College London and his radiology training at Chelsea & Westminster Hospital. He has obtained two post-CCT fellowships in musculoskeletal imaging. He was appointed as a consultant at Chelsea & Westminster Hospital in 2011.

    He has a passion for all sports having worked as a radiologist at the Glasgow Commonwealth Games and London World Athletic Championships and continues to support The Championships, Wimbledon. He also continues to work with a number of Premier League and Championship Football Clubs, Premier League Rugby Clubs, England Sevens Rugby, British Athletics and the Lawn Tennis Association.

    A day in the life of Dr Rajeswaran involves giving his expert opinion on investigations such as MRI and CT scans, x-rays and ultrasound. He also performs injection lists under ultrasound, CT and X-ray including spinal injections. He also regularly teaches and presents at sports medicine conferences.

    Dr Gajan Rajeswaran is an avid football fan and life-long fan of Tottenham Hotspur (for which he offers no apologies!). Outside of work, he spends time with his family and has a keen passion for photography.

    Dr Ajai Seth
    MBBS, BSc, MSc, MRCS, MRCGP, FFSEM
    Medical Director, LBSM
    Consultant in Sport and Exercise Medicine

    Dr Ajai Seth is a Sport and Exercise Medicine Physician. He has dedicated his career to helping people with sport and exercise related injury and illness. He consults and treats everyone from the elite athlete to the weekend warrior.

    Dr Ajai Seth is part of the British Tennis Sports Physician team at the LTA and has also provided cover to elite athletes at Wimbledon Tennis, European Tour Golf, Premier League Football, British Athletics, and the Men’s England Football academies as part of the FA.

    He also prides himself for working in disability sport and is currently the Chief Medical Officer for Team GB Wheelchair Tennis which has taken him to the Olympics and Paralympics.

    Dr Ajai Seth is dedicated to education, training and research and is a Senior Lecturer in Sports Medicine at King’s College London where he lectures in all aspects of Sports Medicine and Science.

    He also has a passion for travel and Expedition Medicine, which has seen him accompany medical, scientific and charity expeditions all around the world. He also has vast experience in treating musculoskeletal injuries from children and adolescents to veteran exercisers, both male and female.

    Dr Seth also has positions in leading Sport Medicine organisations, including the non-executive board for the UK’s largest Sports Medicine charity, BASEM and Past President for the Royal Society of Medicine. 

    A day in the working life of Dr Seth involves consulting his patients in clinic, performing diagnostics and ultrasound guided injections. He also regularly lectures and tutors students and presents at sports medicine conferences internationally. He also spends part of the working week at the National Tennis Centre, LTA, supporting British Tennis players.

    Outside of work, Dr Seth enjoys playing club tennis, triathlon, golf, running and skiing (but will give any sport a go!). He enjoys keeping fit and active and good quality family time with his wife and three children.