3.6.3 Hormonal and neuroendocrine changes in psychiatric disorders

Hormonal Changes in Psychiatric Disorders

Since mood and behaviour are emergent characteristics, it is challenging to concentrate on a physiological level that would be most useful for diagnostic classification. It is now understood that a person’s unique genetic polymorphisms are unlikely to increase their chance of developing psychiatric disorders by more than a very tiny amount. Additionally, it is now understood that the relationship between genes and behaviour includes a variety of mechanisms for modifying risk, including epigenetic change of gene expression and the plasticity of neurons, synapses, and neural networks. Each of these biological processes can be influenced by hormones. Despite occurring at the receptor, metabolism, or synthesis levels, hormonal imbalances can nonetheless assemble into distinct psychiatric disorders.

It can be hard to recognize hormone-related disorders. First, several hormonal changes take place at once throughout spontaneous reproductive hormone fluxes including puberty, the menstrual cycle, pregnancy, lactation, and menopause. Unfortunately, there is a propensity to focus just on oestrogen swings when diagnosing psychiatric symptoms rather than taking into account a wider range of hormonal alterations. Some conditions, such as postpartum OCD, may not fully manifest after exposure to oestrogen or progesterone levels typical of pregnancy. The complicated metabolism of circulating steroid hormones presents yet another significant obstacle in separating out hormonal influences on psychiatric diseases. Because local tissue and cellular enzymes can convert steroid hormones to other molecules with differing functions, such as neurosteroids, circulating hormone levels can differ from levels in particular brain regions or within specific cells. Studying the effects of enzyme inhibitors, receptor antagonists, and hormonal substances that are resistant to metabolism are ways to identify the hormone metabolite closest to symptom development. Finally, the absence of agonists and antagonists that can access the brain as well as distinct hormone pools at different brain regions and in the periphery makes it difficult to examine the psychiatric effects of peptide hormones like oxytocin and inflammatory cytokines.

Mood disorders related to the menstrual cycle and pregnancy:

The standard illustration of a hormonally related mood illness is Premenstrual Dysphoric Disorder (PMDD) or premenstrual mood disorder, which is being considered a new diagnosis for DSM-V. It is characterised by brief, recurrent depressive episodes that start before the menstrual cycle and stop a few days after its onset. Symptoms include oedema, general discomfort and low mood. Luteal hormones cause the symptoms, which are alleviated throughout the follicular phase of the cycle and after hormonal cycling is stopped. Only a small fraction of women experience considerable disability, and symptom severity is ongoing. It is currently unknown whether luteal hormones are felt more strongly by women with PMDD due to anomalies in luteal hormone metabolism or receptors or due to weaknesses in downstream systems impacted by luteal hormones (Altemus, 2010).

Maternity blues occurs within the first few days postpartum. It often ends by the second week. Symptoms include low mood, irritability, crying episodes and general fatigue.

Postpartum psychosis often starts within 2 weeks postpartum. Characterised by mood changes and delusions focused on the newborn. The mainstay of treatment is admission to the mother-baby unit under specialist psychiatric care.

Thyroid hormone disorders and their psychiatric features:

The hypothalamic-pituitary-thyroid axis and its associated feedback mechanisms regulate thyroid hormone levels:

Hyperthyroidism is most commonly caused by Grave’s disease. Clinical features include palpitations, tachycardia, irritability, fine tremor, reduced appetite with weight loss and generalised anxiety associated with panic disorder. In primary hyperthyroidism, free thyroid hormone levels are raised, with low TSH levels. This is because of the negative feedback on the pituitary gland.

Primary hypothyroidism accounts for over 90% of hypothyroidism cases. Lithium a common psychiatric medication is one of the causes. Clinical features include dry skin, reduced reflexes, bradycardia, cold intolerance, weight gain with reduced appetite and menorrhagia in women. A common psychiatric feature is a depression often with cognitive disturbances. In hypothyroidism, free hormone levels are low and TSH levels are raised due to the loss of the negative feedback effect.

Thyroid disorder:	Free thyroid hormone level:	TSH level:
Primary hyperthyroidism	Raised	Low
Hypothyroidism	Low	Raised

Adrenal gland insufficiency and psychiatric disorders:

The adrenal glands which are regulated by the hypothalamic-pituitary-adrenal (HPA) axis secretes cortisol, aldosterone and sex steroids. Increased activity of the HPA axis is noted in both stress and depression. A combined dexamethasone/corticotropin-releasing hormone test (DEX/CRH-test) determines the function of the HPA axis. Often psychiatric patients have raised cortisol and ACTH post administration of dexamethasone.

Cushing’s syndrome is associated with raised cortisol levels. Clinical features include plethoric complexion, purple striae, proximal muscle weakness, buffalo hump, hypertension and central obesity. Depression and cognitive changes are common psychiatric features. Often they will resolve once cortisol levels normalise.

Addison’s disease has a number of causes, with the most common in the developing world being autoimmune destruction of the adrenal gland. Clinical features include hyperpigmentation in palmar creases, weight loss, vitiligo, gastrointestinal symptoms and salt cravings. Depression, apathy and memory impairment are common psychiatric features. Hyponatraemia and hyperkalemia occur due to a loss of aldosterone function in kidney tubules.

Suprachiasmatic nucleus and the pineal gland:

The ‘physiological internal clock’ functions with both the suprachiasmatic nucleus and the pineal gland. The suprachiasmatic nucleus stimulates pinealocytes, or pineal gland cells, to produce melatonin, which helps to initiate and maintain sleep patterns.

Circadian rhythm sleep disorder is a consequence of there being a mismatch between sleep requirements dictated by social activities and the body’s internal clock. Clinically we prescribe synthetic melatonin with the aim to help reset the biological clock by reorganising the circadian rhythm.

Seasonal affective disorder: is a mood disorder subset, in which people who have normal mental health throughout most of the year exhibit depressive symptoms at the same time each year. A theory associated with this disorder is that the cause is related to melatonin, which is produced by the pineal gland in dim light and darkness because there are direct connections between the retina and the pineal gland via the retinohypothalamic tract and the suprachiasmatic nucleus. The endogenous circadian clock regulates melatonin secretion, although it can also be repressed by intense light.

Gonadal hormone dysgenesis and psychiatric disorders:

Gonadal dysgenesis has been attributed to the cause of Klinefelter syndrome and Turner syndrome. Hypogonadotropic hypogonadism is seen due to primary gonadal failure.

Klinefelter syndrome: is characterised by tall stature, reduced facial hair, gynaecomastia and infertility in males. The cognitive function is impaired with mild to moderate intellectual function.

Turner syndrome: is characterised by a webbed neck, small stature, heart abnormalities, cubitus valgus, and skeletal abnormalities in females. The cognitive function may be intact.

Growth hormone disorder and psychiatric features:

Growth hormone secretion by the pituitary gland is regulated by the hypothalamus. Growth hormone promotes growth and exerts metabolic action on the liver, adipose tissue and skeletal muscle.

Hypopituitarism (when you have a short supply (deficiency) of one or more of the pituitary hormones) will result in marked depression and apathy.

Anatomy of the Neuroendocrine System

The Hypothalamus:

Location: The hypothalamus lies on each side of the 3rd ventricle above the midbrain and below the thalamus.

Function: Regulates homeostatic functions of the human body. Plays a role in circadian rhythm and in response to mood.

Hormones: Synthesises and secretes neurohormones/neuropeptides, which control the subsequent release of pituitary hormones. The hypothalamus releases thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GnRH), growth hormone-releasing hormone (GHRH), corticotropin-releasing hormone (CRH), somatostatin, and dopamine into the circulation, where they travel to the anterior pituitary (Shahid 2020).

The Pituitary gland:

Location: The pituitary gland lies in the sella turcica in the sphenoid. It is inferior to the hypothalamus and connected by the infundibulum.

Structure: The pituitary gland is made up of the anterior and intermediate lobes, named the adenohypophysis, and the posterior lobe, named the neurohypophysis.

Function: Regulates functions relating to metabolism, growth, reproduction, and lactation and is associated with the stress response.

Hormones: The anterior pituitary gland secretes: growth hormone (GH), prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), thyroid-stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH). Whilst the posterior pituitary gland (neurohypophysis) secretes oxytocin and antidiuretic hormone (ADH) or vasopressin.

Neuroendocrine Changes in Psychiatric Disorders

Type 2 diabetes and obesity continue to be significant public health problems, with type 2 diabetes rates increasing at an epidemic rate. It is critical to find new risk variables that may inspire the creation of innovative preventative strategies because known risk factors do not fully account for population variation. Depression and chronic psychological stress are linked to type 2 diabetes, however, the exact mechanism is yet unknown. A common reason could be that these stressors cause neuroendocrine alterations, notably stimulation of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis.

Psychiatric features of diabetes mellitus:

People who suffer from diabetes mellitus have higher rates of psychiatric disorders. People with depression are poorly motivated to follow strict dietary regimes and maintain glycaemic control.

Antipsychotics such as clozapine are associated with an increased risk of diabetes mellitus. The CATIE trial demonstrated that Olanzapine was associated with greater weight gain, hyperlipidemia, and hyperglycemia.

References:

(1) Shahid, Z., Asuka, E. and Singh, G. (2022). Physiology, Hypothalamus. [online] PubMed. Available at: https://www.ncbi.nlm.nih.gov/books/NBK535380/#:~:text=The%20thyrotropin%2Dreleasing%20hormone%20(TRH.

(2) El, S.A., Fahmy, M.W. and Schwartz, J. (2019). Physiology, Pituitary Gland. [online] Nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK459247/.

(3) Moore DP, Puri BK (2012). Textbook of Clinical Neuropsychiatry and Behavioural Neuroscience (3rd edition), pp. 534-542. CRC Press.