Corticosteroids: the ‘floating switches’ that ‘ignites’ the physiological ‘engine’

 Nature has quaint ways of  doing its job. The nervous system of an organism takes cues from the environment and initiates a well crafted, precisely timed sequence of events (See someone nudging the ball and set it rolling down the hill) to adjust to the surroundings. The environment is a bountiful of stressors. In addition to the promptly generated neuronal response, a slow and sustained adaptive mechanism drives the forces of ‘struggle and survival’ in the living organism. The Hypothalamus-Pituitary takes the ‘lead and first role’ in ‘pushing the ball down the hill’ and a relay run begins. The corticotropin releasing hormone from the hypothalamus ‘runs’ to the pituitary; the pituitary in turn continues the relay run by releasing corticotropin (also commonly known as ACTH); ACTH ‘runs’ to the adrenal cortex which releases the adrenal corticosteroids. Adrenal corticosteroids are of two types- the glucocorticoids and the mineralocorticoid. The most well known endogenous glucocorticoid and mineralocorticoid are cortisol and aldosterone respectively. The ‘run’ ‘stops’ at the adrenal cortex from where the adrenal cortisol hormones are disseminated to every nook and corner of the body. The actions of corticosteroids are widespread but tissue dependent. The corticosteroids act as ‘floating switches’ ready to ‘ignite’ the ‘flames’ of cellular processes in the cells which have the ‘matching switches’ in the respective cells. The ‘matching switches’ are the glucocorticoid receptors (GR) and the mineralocorticoid receptors (MR). Both the GRs and MRs are intracellular cytoplasmic receptors. The GRs are ubiquitous and are responsible for translation of most of the actions of the glucocorticoids through the glucocorticoid response elements (GRE). The MRs are present in kidneys, hippocampus and colon. The glucocorticoids can also bind with MRs, in fact, with much greater affinity than the mineralocorticoid and can result in manyfold higher activation of mineralocorticoid response elements (MRE). Fortunately, nature has bestowed a mechanism to prevent the excessive action of glucocorticoids in such cells. The glucocorticoids are selectively inactivated by the enzyme 11 hydroxysteroid dehydrogenase and only the mineralocorticoid are available for action.

The drug that saved lives in COVID 19

 The debate of using steroids in ARDS secondary to infective etiology has been raging since the inception of the concept, when at the fag end of 2019, a virus, SARS COV2, emerged as the one of the deadliest ever in the history of human civilisation. Desperate situations need desperate measures. And once again, in the desperate bid to save lives, mankind turned to steroids in the hour of crisis. The results were not miraculous but optimistic. Patients who were critically ill requiring oxygen or mechanical ventilation seemed to benefit from the new weapon in the armamentarium. This occurred at a stage when the performance of the ‘big warriors’ viz. the antivirals remained below expectation. The ‘hope’ in the hour of darkness resulted in the worldwide use of steroids on a massive scale, sometimes even, over enthusiastic and premature. Reports of secondary infections attributed to steroid induced immunosuppressive started emerging, but the exact cause of the phenomenon remained an enigma. Over time, the use of steroids in COVID with pulmonary devitalisation has become a global consensus. Considered to be the ‘game changer’ in the management of seriously ill COVID-19 with lung injury, the surfacing results of the ongoing and completed studies have already proved its usefulness in the fight against the worst pandemic in history. With time, the virus is expected to weaken and human zeal to live and love will sweep the  tragedies into oblivion. However, science and society will for ever preserve the ‘treasure’ of the powerful medicine that is a ‘two edged sword’, but when used judiciously to ‘strike the iron when it is hot’ can save lives and ‘do no harm’.

The buried mystery of oestrogen effects in post menopausal women

 The cardiovascular protective effect of estrogen in premenopausal women is assumed to be due to improvement in HDL:LDL ratio, diminished atherogenesis and improved vascular health attributed to NO and PgI. These factors formed the basis of their use in postmenopausal women for better cardiovascular outcomes. Indeed, estrogens provide cardiovascular protection in early post menopause but with advancement of age, the protective effects wane. In the year 2002, the findings of the landmark trial, Women's Health Initiative, showed for the first time that the risks associated with HRT outweigh the benefits and henceforth, the popularity of HRT declined rapidly. The real world evidence generated from the trial was enough to overwhelm the popular pharmacological concepts of estrogenic  cardiovascular benefits and ever since the mechanism of estrogenic effect in postmenopausal women has remained a mystery. Perhaps, it will be never be possible to know, because estrogens are no longer given to postmenopausal womem for long years. The use has become restricted for vasomotor symptoms and atrophic vaginitis. They are given for the shortest possible time in the smallest possible dose. At present, we can only speculate the possible reasons for adverse cardiovascular effect of estrogen in post menopausal women. One reason may be that estrogen increase the synthesis of clotting factors in the liver and that may be responsible for increased incidents of deep vein thrombosis, acute myocardial infarction etc. But then, why they don't increase the cardiovascular risk in premenopausal women, no body knows. There are many mysteries of nature which are yet not known to mankind.

The history of use of hormone replacement therapy in post menopausal women

 Estrogens are cardio protective. The cardiovascular health of women is seen to be better than their male counterparts till the date when menopause sets in and the level of the sex hormones declines in women. The development of pharmaceutical expertise to separate and purify the female sex hormones in the early part of the twentieth century opened vistas for their use in post-menopausal women. Very soon, hormone replacement therapy become widely popular for improving the physical, psychological and cardiovascular health of post-menopausal women. It was known long before that unimpeded estrogenic action results in endometrial proliferation and increases the risk of endometrial carcinoma. Therefore, from the very beginning, hormone replacement therapy involves the use of progesterone in a cycle manner along with oestrogen. Numerous observational studies showed the benefits of HRT on the cardiovascular health of women.The use of hormone replacement therapy for presumed cardiovascular benefit continued for many years. For the first time, a study sponsored by the National Institute of Health, the Women’s Health Initiative showed that Hormone replacement therapy is associated with increased cardiovascular morbidity. The landmark study resulted in the drastic decline of hormone replacement therapy in post-menopausal women. The present recommendation of HRT in post-menopausal women is restricted to control of vasomotor symptoms and atrophic vaginitis in early menopause and should be withdrawn as early as possible. HRT has also been found to increase breast cancer, gallstones and migraine.

 

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