Introduction

Definitions:

AchardThiers syndrome (also known as diabetic-bearded woman syndrome) is a rare disorder mainly occurring in postmenopausal women. It is characterised by type II diabetes mellitus, cushing syndrome and signs related to the overproduction of androgens.¹

The disease is named after French physicians Emile Achard and Joseph Thiers, who first described it in 1921. French physicians Emile Achard and Joseph Thiers reported the first observation of co-existing hirsutism and diabetes and related syndrome to the hyperplasia of the adrenal cortex, detected at autopsy.²

Epidemiology and demographics:

• Prevalence: It is a very rare condition, and hence there is no regularity in data, and thus not well documented
• Gender: It mostly affects females, specifically postmenopausal women
• Age: Women aged between 45 and 55, especially those with menopausal, are likely to develop the disease
• Race: There is no clear confirmation of the occurrence of this syndrome in a particular race

Pathophysiology of Achard-Thiers Syndrome

Genetic Factors

• Genetics plays an important role in the development of type 2 diabetes. The condition often involves insulin resistance, where cells don't respond normally to insulin, leading to a decrease in sugar uptake in the cell, and a buildup in the blood
• The regulation of cortisol production is greatly influenced by genes

Hormonal and Metabolic Abnormalities

Androgen levels in women are regulated by the hypothalamic-pituitary-ovarian axis and the hypothalamic-pituitary-adrenal axis.

Hypothalamic-pituitary-ovarian axis system

• Studies show that excessively high levels of Insulin in the blood, often associated with the conditions of Insulin-resistant Diabetes mellitus Type II, stimulate the ovary for overproduction of androgen³
• The normal female also produces androgens, but in small quantities by theca cells. These are located in the ovarian follicles, which are the functional units of the ovaries involved in the maturation of eggs and sex hormone production
• These theca cells produce androgen hormones in response to the luteinizing hormone (LH) produced by the pituitary gland 
• These androgens can be transported to granulosa cells in the ovaries, where they are converted into estrogens under the influence of FSH via the enzyme aromatase
• In the case of Achard-Thiers syndrome, the overproduced androgens are not fully converted into estrogens because of insufficient activity of aromatase, resulting in elevated androgen levels.
• Two peripheral organs, the liver and the skin, play key roles in the metabolic clearance of these androgens from the circulation
• Abnormalities in the metabolic clearance of ovarian androgen by the liver and the skin can contribute to the severity of androgenism

Hypothalamus-pituitary-adrenal axis system

• The Hypothalamus releases corticotropin-releasing hormone (CRH) in response to stress and other stimuli
• CRH activates the pituitary gland to secrete Adrenocorticotropic hormone (ACTH)
• Hence, ACTH stimulates the adrenal gland and produces cortisol hormone, along with Dehydroepiandrosterone (DHEA) and Androstenedione are the precursors that are converted into androgens or estrogens in peripheral tissues
• Cortisol, stimulated by ACTH, increases blood glucose levels by promoting gluconeogenesis (the production of glucose from non-carbohydrate sources) in the liver and inhibiting glucose uptake in peripheral tissues⁴

Bone Health and Achard-Thiers Syndrome

Effect of Androgens on Bone Health

Estrogen aids to maintain bone density by promoting the development of bone cells.⁵ Low estrogen levels, as seen in menopause, can lead to increased bone resorption (the process by which bone is broken down and its minerals released into the bloodstream). After menopause, the estrogen level falls, resulting in decreased bone density and an increased risk of osteoporosis. 

Effect of Cortisol on Bone Health

• Cortisol, a glucocorticoid hormone produced by the adrenal glands, plays a significant role in bone metabolism. Cortisol inhibits the function and cell division of osteoblasts, the cells responsible for bone formation. Elevated cortisol levels lead to reduced bone formation
• Cortisol also reduces the absorption of calcium in the intestines and increases calcium excretion in the kidneys, leading to inadequate calcium levels available for bone
• Cortisol inhibits the synthesis of collagen, an essential component of the bone matrix, leading to weaker bone structure

Effect of Diabetes on Bone Health

• High sugar levels in the blood result in the production of Advanced Glycation End-products (AGEs). AGEs are harmful end-product compounds that are formed when proteins or lipids get glycated as a result of exposure to sugars. AGEs form bonds with collagen, a major structural protein in bones⁶
• This bond makes the collagen stiffer and less flexible, leading to a more brittle bone matrix and prone to fractures
• AGEs bind to the cell receptor of bone, triggering inflammatory responses. This inflammation promotes bone degradation and impairs bone health

Clinical Manifestations

 Symptoms related to bone health 

• Joint Pain
• Increased fracture incidence
• Osteoporosis
• Osteopenia

Diagnostic criteria

Clinical History

• Diabetes mellitus
• Obesity
• Cushing’s syndrome is caused by a high cortisol level

Biochemical Testing

• 24-hour urinary free cortisol test
• late-night salivary cortisol test
• A two-hour oral glucose tolerance test.

Imaging studies

X-ray- Low Bone Mineral Density (BMD) is detected through dual-energy X-ray absorptiometry (DEXA) scans, indicating osteoporosis, or osteopenia.

Interventions 

Pharmacological and Surgical Treatments 

• Medications like Ketoconazole, mifepristone, metyrapone, etomidate, or mitotane can help to reduce excessive cortisol production
• Medications like bisphosphonates, calcitonin, or denosumab may be used to prevent further bone loss and manage osteoporosis
• Calcium is absorbed in the presence of vitamin D, so it is important to ensure taking the Vitamin D supplement with Calcium
• Metformin, Insulin therapy, SGLT2 inhibitors like canagliflozin, dapagliflozin, or GLP-1 Receptor Agonists like liraglutide, and semaglutide to control diabetes
• In cases where adrenal tumours or hyperplasia are causing excess cortisol production, surgical removal of the adrenal glands (adrenalectomy)may be necessary
• Surgical removal of ACTH-secreting pituitary tumours, if present
• Hydrocortisone and Prednisone. In case of adrenalectomy, hydrocortisone may be used to replace cortisol. This helps manage symptoms of adrenal insufficiency and maintain normal physiology

Lifestyle modifications 

Diet and nutrition

• Ensure sufficient intake of calcium and Vitamin D to support bone health. Foods rich in calcium, such as dairy products, leafy green vegetables, and fortified foods, should be consumed daily
• Vitamin D can be obtained from sunlight exposure and supplements if needed
• Consuming foods rich in antioxidants can help oppose oxidative stress related to AGEs and protect bone health
• Adopting cooking methods such as steaming, boiling, or poaching can help reduce exogenous AGE intake

Physical activity and exercise

• Physical activity like weight-lifting and muscle-strengthening exercises such as walking, jogging, dancing, and resistance training can contribute to building and maintaining bone density
• Avoiding smoking and alcohol consumption can also help reduce AGE formation and maintain bone health

Summary

Achard-Thiers syndrome is a rare condition characterised by the combination of high levels of cortisol and androgen and diabetes mellitus. Excessive production of cortisol by the adrenal gland leads to symptoms such as obesity, hypertension, diabetes, and skin changes.

High blood sugar levels are due to insulin resistance or insufficient insulin production.

The syndrome often manifests in middle-aged menopausal women and is linked to prolonged exposure to high levels of cortisol. Treatment usually focuses on managing the underlying causes of elevated cortisol levels and controlling blood sugar levels.