Neuroendocrinology Mini-Review

8 May 2017

Metformin treatment for diseases aside from Diabetes: Focus on Addison’s disease, adrenal glands and thyroid glands

Word count: 2856

Abstract:

Adrenal insufficiencies lead to increased rates of morbidity and mortality. In order to address these insufficiencies, glucocorticoid replacement has been the primary treatment of choice. However, side effects are intense and patients are more prone to developing metabolic complications. Therefore, this has lead researchers to look for alternate treatments and one that has been repeatedly experimented with is metformin. Metformin is most commonly used and known for the treatment of diabetes. However, studies have shown that it has also contributed to alleviating symptoms and side effects of corticosterone treatments, especially in Addison’s disease and Polycystic ovary syndrome (PCOS). In Addison’s disease, there is not enough cortisol and aldosterone hormone production, and in PCOS, high levels of plasma concentration of androgen and insulin resistance is common. Metformin’s mechanism of action occurs in the liver and peripheral tissues and functions to reduce the amount of gluconeogenesis, glucose secreted, and fatty acid synthesis from the liver, while simultaneously enhancing the glucose uptake and fatty acids oxidation of the peripheral tissue when it is needed. Each individual patient will react differently to the treatments however, the majority from tests and clinical trials have shown a decreased state of adrenal insufficiency. Metformin has also shown to alleviate thyroid problems, specifically with the production of thyroid stimulating hormone (TSH), Triiodothyronine, T3, and Thyroxin, T4, as well as patients with insulin resistance and thyroid nodules on thyroid glands.

Introduction:

Addison’s disease is the result of the lack of cortisol and aldosterone hormone production from the adrenal cortex of the adrenal glands in the body. Cortisol’s primary function is to assist the body in its response to stress and it is produced in the middle layer of the adrenal cortex. It also controls the usage of macronutrients, and helps maintain blood pressure and control inflammation. Aldosterone assists the kidneys in regulating sodium and potassium ions in the blood, and water and electrolyte balance in the body. Addison’s disease is also known as primary or secondary adrenal insufficiency, which can be life threatening in all age groups and sexes (Dorin et al, 2003). In primary adrenal insufficiency, the adrenal glands do not produce enough of the hormone cortisol. In secondary adrenal insufficiency, there is a problem with the signal that the brain sends to the adrenal glands instructing them on how to make cortisol. This can also happen with people who consume corticosteroids for treatment of chronic conditions such as asthma or arthritis and abruptly stop consumption. Once these hormone levels start to decrease, symptoms begin to appear and include irritability, extreme fatigue, low blood pressure, low blood sugar (hypoglycemia), depression, muscle or joint pains, weight loss and decreased appetite, salt craving, nausea, diarrhea, vomiting, darkening of skin, as well as body hair loss or sexual dysfunction in women. In the case of acute adrenal failure, also known as addisonian crisis, which can be caused by an injury, infection or illness, or a physical stress, symptoms such as pain in your lower back, abdomen or legs, severe vomiting and diarrhea, high potassium and low sodium, low blood pressure, and loss of consciousness may appear suddenly. At 70% of the time, the primary cause of an autoimmune disease, where the body attacks itself, is due to failure of the hormones production from the adrenal glands. This can be a result of tuberculosis, HIV, spread of cancer, other infections, and bleeding into the adrenal glands. Tuberculosis is the most common cause of Addison’s disease worldwide, and is a bacterial infection that affects the lungs and other parts of the body and can damage the adrenal glands. The adrenal glands will provide the steroid hormones of cortisol and aldosterone until 90% of the adrenal cortex is destroyed. This mini-review primarily focuses on the alternative method that metformin provides in response to the effects of glucocorticoid treatment in diseases such as Addison’s disease which deals with the adrenal glands and as well as its implications in diseases related to the thyroid gland.

Neuroendocrinology of adrenal glands:

The adrenal glands are two organs located on top of each kidney. They have two primary parts, the outer part known as the adrenal cortex, and the inner part known as the adrenal medulla. Each part secretes different hormones. The adrenal cortex produces glucocorticoids, which is triggered by the hypothalamus and the pituitary gland, and mineralocorticoids which are released by signals from the kidney. The lack of, or hyposecretion, of the adrenal cortex hormones begins at the hypothalamus where corticotropin releasing hormone (CRH) is released into the pituitary gland. The pituitary gland is then activated to secrete adrenocorticotropic hormone (ACTH) into the adrenal glands which then releases glucocorticoids such as cortisol and catecholamines such as epinephrine, norepinephrine, and aldosterone. This pathway is called the hypothalamic pituitary adrenal (HPA) axis. However, when there is an abnormality in the negative feedback mechanism, the secretion of CRH or ACTH is shut off or the intensity is lessened which leads to the hyposecretion of cortisol and aldosterone. The deficit in ACTH can lead to secondary adrenal insufficiency and a deficiency in CRH due to an injury in the hypothalamus. This also leads to a lesser production of cortisol in the adrenal glands and can potentially become an adrenal insufficiency. Primary adrenal insufficiency is typically due to a damaged part of the adrenal cortex which is the outer layer of the adrenal glands.

Treatment of adrenal insufficiency:

Typical treatments commonly include daily medications that replace the lack and loss of hormones. Aldosterone is replaced with an oral mineralocorticoid, commonly known as fludrocortisone, as well as a doctor’s recommendation of an increased sodium intake.

Cortisol is replaced with an oral synthetic glucocorticoid or an oral hydrocortisone and is taken once or twice a day in order to provide the minimum amount of glucocorticoid needed to replace the body’s natural cortisol production levels (Johannsson et al, 2012). Glucocorticoids bind to glucocorticoid receptors in the cytoplasm which are a type of nuclear receptor that is activated by ligand bonding. They may increase the transcription of genes coding for anti-inflammatory proteins or result in the regulation of gene expression. This mechanism is commonly known as Transactivation (Figure 1). Glucocorticoids inhibit the expression of multiple inflammatory genes and is mostly due to a direct inhibitory interaction between activated glucocorticoid receptors and activated transcription factors. It is also common that glucocorticoids change the chromatin structure and interact with CREB-bind protein which is a co-activator of transcription (Matfin, 2010).

 

Figure 1: Transactivation of glucocorticoids. Cortisol binds to the glucocorticoid receptor (GR) in the cytoplasm, after which the ligand-bound GR can migrate into the nucleus. The GR binds to glucocorticoid-response element (GRE) to transactivate gene expression.

These glucocorticoids are a type of corticosteroids which are a class of steroid hormones, hormones made in the adrenal cortex. Steroid hormones help control metabolism, inflammation, immune function, salt and water balance, and more in their target cells. They are known to be lipophilic and readily cross the lipid cell membrane in order to recognize and bind to a particular protein receptor. Once this binding occurs, the steroid-receptor complex binds to DNA and manages to increase or decrease the transcription of specific genes and have the ability to switch on a gene for synthesis of a certain protein. They are effective in stopping damaging inflammation caused by many immune system disorders as they are part of the feedback mechanism in the immune system that reduces certain aspects, of immune function. Addisonian or adrenal crisis requires more urgent medical attention, and can be fatal if not treated correctly and quickly. Treatment commonly includes an intravenous injection of glucocorticoid, salt water (saline) and sugar (dextrose) in order to stabilize the patient. While Addison’s disease is a rare but serious disorder, most patients live normal lives and medications that help to boost cortisol hormone levels are required for life and can help the patient feel healthy. However, there are occurrences where too much of these medications lead to unwanted and harmful side effects. Blood sugar levels can be increased and trigger diabetes, suppress the ability to absorb calcium leading to osteoporosis, increase cholesterol and triglyceride levels, increase risk of ulcers and gastritis, delay of healing in wounds, and suppress the immune system and make individuals more prone to infections. The new and more comprehensive understandings of glucocorticoid mechanisms may lead to the development of novel steroids with a lesser risk of side effects. A study was done to develop a once-daily (OD) oral hydrocortisone dual-release table with a more physiological exposure-time cortisol profile in order to decrease the morbidity and mortality rate of patients with adrenal insufficiencies. 64 adults with a primary adrenal insufficiency were compared after half were given conventional TID (thrice-daily) and the experimental group, OD.  The OD treatment showed a sustained serum cortisol profile after the morning intake and reduced the late afternoon and the 24-hour cortisol exposure. There was a decrease in the mean weight, systolic, and diastolic blood pressure and improved glucose metabolism after 12 weeks (Johannsson et al, 2012).

Metformin as choice of drug to combat glucocorticoid therapy side effects:

Metformin is a novel treatment in the case of using it outside of diabetic medication. According to Korbonits et. al, from the London NHS Trust, nearly 1% of the general population is treated with long-term glucocorticoids. Currently, multiple clinical trials are in process. Metformin is one of the most widely prescribed antihyperglycemic agents for diabetes. Compared to other medications, it is unique because of its effect on glycemic control by addressing insulin resistance. It is most commonly used to treat diabetes, however it has been proven to help other diabetes associated conditions such as polycystic ovary disease, cardiovascular issues, and unbalanced thyroid function levels. Metformin’s mechanism of action occurs in the liver and peripheral tissues and functions to reduce the amount of gluconeogenesis, glucose secreted, and fatty acid synthesis from the liver, and simultaneously enhance the glucose uptake and fatty acids oxidation of the peripheral tissues ( et al, 2017).  Different studies have led to show how metformin can affect various parts of the body leading to available treatments for diseases. In an animal model, investigators have shown that by altering adenosine-monophosphate-activated protein (AMPK) activity, metformin prevents the development of metabolic complications of glucocorticoid excess (Korbonits et. Al). In a human study, a double-blind, placebo-controlled trial, patients who were beginning glucocorticoid treatments were randomized to receive a certain amount of metformin each week and the other group, a placebo. All patients underwent a baseline and a four-week assessment and in the first trial of targeting metabolic complication in patients needing glucocorticoid therapy, there was a beneficial effect of metformin on glycemic control in 29 of 34 randomized non-diabetic patients at the completion of the trial (Seelig et Al, 2017).

Figure 2: Metformin’s effects on different glands of the body

Organ Metformin Effect
Liver Decreases hepatic glucose production
Skeletal muscle Improves peripheral glucose uptake
Pancreas Improves insulin secretion
Fat Improves peripheral glucose uptake
Gut Decreases appetite and caloric intake

 

Metformin’s effects in TSH axis

Interestingly, studies have shown the effects of metformin on other parts of the endocrine systems as well. In the thyroid gland, it affects TSH, thyroid stimulating hormone, but a lack of effect on the thyroid hormones T3, Triiodothyronine, and T4,, Thyroxin. This raises interest as the HPT (hypothalamic-pituitary-thyroid) axis secretes TSH from the anterior pituitary to the thyroid gland which is then activated to secrete T4, and T3 which increases or decreases metabolism. In the regular feedback mechanism of the HPT axis, a change in TSH regularly leads to a change in T4, and T3 levels. High levels of TSH without change in T4,and T3 can be referred to as subclinical hypothyroidism. In the recent study of Cappelli et al, patients with existing hypothyroidism were started on metformin and for their levels of T4, and T3 remained unchanged over one year but demonstrated a statistically significant difference in the level of TSH (P < 0.05) while the euthyroid patients had an unchanged TSH. Another study done by Vella S. et al from Malta studied 138 individuals with type 2 diabetes where about half were on metformin. TSH was lower in the metformin treated patients and T4, was higher in the females who were on metformin compared to the control group. Both studies concluded that metformin is likely affecting the thyroid function through inhibition of the peripheral conversion of thyroxine to triiodothyronine (Abdelgadir et al, 2017). It has also been shown that patients with insulin resistance (IR) have a higher prevalence of thyroid nodules and bigger thyroid glands (Rezzónico et al., 2011). 66 women with IR and nodular hyperplasia were separated into four different groups which consisted of group one being treated with metformin, group two treated with metformin and levothyroxine (L- T4,), thyroid medicine that treats hypothyroidism, group three treated with L- T4, and group four without any treatment. The results showed that group two and three dropped in TSH levels, group one and two normalized the homeostasis model assessment (HOMA) index after treatment, and group one and two, the two groups that contained metformin, showed significant reduction in the nodule sizes while patients from group three and four did not have any significant reduction in nodule sizes. Rezzónico et al. concluded that metformin produced a significant decrease in the nodular sizes in patients with IR and small thyroid nodules.

Effects of Metformin on Polycystic Ovary Syndrome:

Polycystic ovary syndrome (PCOS) is an endocrine system disorder among women that can include enlarged ovaries that contain small collections of fluid. This can lead to infrequent or prolonged menstrual periods, excess hair growth, acne, and obesity. In patients with PCOS, high levels of plasma concentration of androgen and insulin resistance is common. Hyperinsulinemia in women with PCOS affects adrenal production by an increase in ACTH secretion. Metformin is associated with increased menstrual cyclicity, improved ovulation, and a reduction in circulating androgen levels. Fourteen women who were diagnosed with PCOS and had less than six menstrual periods in the previous year, were studied according to their plasma concentrations of progesterone and were administered ACTH to obtain blood samples. Metformin was then given at a dosage of 500 mg, three times a day for 30 days. The administration lead to ovulation occurring in 2 women (14%) and no significant change in basal levels of cortisol or in the response of cortisol in response to the month of metformin therapy. (Marca A. et al, 1999). Findings included that metformin caused the reduction in basal plasma concentrations of free testosterone and in the adrenal secretion of androgens in response to ACTH and reducing insulin levels. This study mainly agreed that the main effect of metformin was on the liver with increased secretion of sex hormone-binding globulin (SHBG and the reduction in free testosterone was most likely a secondary effect. Another study aimed to use a double-blind, placebo controlled with detailed assessment of ovarian activity such as two blood samples per week to assess the validity of metformin therapies. Out of 94 patients, 45 received metformin, the rest placebo. There was a rapid effect of follicular maturation and an inverse relationship between body mass and treatment efficacy in the metformin therapy group after fourteen weeks in comparison to the placebo therapy group. It is conclusive that metformin provides a beneficial effect on improving ovarian function in women with polycystic ovaries by increasing ovulation rates as well as significant weight loss and an associated change in high-density lipoprotein (HDL) cholesterol (Fleming et al, 2002).

Conclusion:

So far, the replacing of the lack of cortisol and aldosterone is the best known solution for Addison’s disease. However, the uprising goal is to find a treatment that does not have as many troubling side effects, or to find a way to correct the lack or loss of signal(s) throughout the HPA axis. So far, metformin has provided promising results that ameliorate the effects of corticosterone treatment in Addison’s disease as well as regulating ovarian function in women with Polycystic Ovary Syndrome. In relation to the thyroid gland and the HPT axis, metformin’s ability to lower TSH without changing T3 and T4 levels continues to be instrumental in helping individuals with type 2 diabetes. Also in the thyroid gland, metformin has helped reduce the size of thyroid nodules in patients with insulin resistance. There are some other beginning research and clinical stages for alternate metformin uses such that include it as an anti-inflammatory agent, an anti-oxidant, improving endothelial function, a weight reducing agent, the nervous system, blood homeostasis, HIV treatment-related side effects, and cancers which includes liver, pancreatic, breast, colorectal, prostate, lung, thyroid, endometrial cervical, renal cell, and melanoma. This has made metformin one of the most prescribed antihyperglycemic agents and even though it is one of the older drugs that has been on the market for a while, it continues to provide some of the best results due to its effect on glycemic control by addressing insulin resistance. Further interest and studies need to be conducted in order to gain full understanding and explanation of how metformin can have all of these effects on a variety of symptoms.

 

References:

Abdelgadir, E., Ali, R., Rashid, F., & Bashier, A. (2017, May). Effect of Metformin on Different Non-Diabetes Related Conditions, a Special Focus on Malignant Conditions: Review of Literature. Retrieved April 20, 2017

Barnes, P. J. (1998, June). Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Retrieved April 06, 2017

Barts & London N&H Trust. (n.d.). Prevention of Metabolic Complications of Glucocorticoid Excess. Retrieved April 06, 2017

Dorin, R. I., Qualls, C. R., & Crapo, L. M. (2003, August 05). Diagnosis of Adrenal Insufficiency. Retrieved May 08, 2017,

Fleming, R., Hopkinson, Z. E., Wallace, A. M., Greer, I. A., & Sattar, N. (2002, February 01). Ovarian Function and Metabolic Factors in Women with Oligomenorrhea Treated with Metformin in a Randomized Double Blind Placebo-Controlled Trial. Retrieved April 20, 2017

Johannsson, G., Nilsson, A. G., Bergthorsdottir, R., Burman, P., Dahlqvist, P., Ekman, B., . . . Skrtic, S. (2012, February 01). Improved Cortisol Exposure-Time Profile and Outcome in Patients with Adrenal Insufficiency: A Prospective Randomized Trial of a Novel Hydrocortisone Dual-Release Formulation. Retrieved May 08, 2017

Marca, A. L., M.D., Morgante, G., M.D., Paglia, T., B.Sc., Ciotta, L., M.D., Cianci, A., M.D., & Leo, V. D., M.D. (1999, December). Effects of metformin on adrenal steroidogenesis in women … Retrieved April 20, 2017

Matfin, G. (2010, June). Something old, something new…. Retrieved April 06, 2017

Seelig1*, E., Meyer1*, S., Timper12, K., Nigro1, N., Bally3, M., Pernicova4, I., . . . And, M. K. (2017, March 01). Metformin prevents metabolic side effects during systemic glucocorticoid treatment. Retrieved April 06, 2017

Rezzónico, J., Rezzónico, M., Pusiol, E., Pitoia, F., & Niepomniszcze, H. (2011). Metformin treatment for small benign thyroid nodules in patients with insulin resistance. Metabolic syndrome and related disorders9(1), 69-75.

Seibel, M. J., Cooper, M. S., & Zhou, H. (2013). Glucocorticoid-induced osteoporosis: mechanisms, management, and future perspectives. The Lancet Diabetes & Endocrinology1(1), 59-70.

 

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