The Exaptation of Endocrine Pharmacology

Exaptation means the utilization of a trait, whether anatomical or behavioral, for a function different from what it was originally meant for. This term was originally meant to explain concepts of evolutionary biology and was coined in 1982 by Gould and Vrba. For example, birds initially evolved feathers for temperature regulation, but later exapted them for display and flight. The term exaptation can be utilized to describe the off-label uses and benefits of various drugs. A molecule developed for a particular indication, for example, can be found to have other actions and benefits, both expected and unexpected. Using the drugs to harness these actions, and achieve these benefits, can be termed as pharmacologic exaptation.

The development of endocrinology has been linked, default with the growth of endocrine pharmacology. Though research related to glands and their secretions had begun much earlier, the science gained interest and popularity only when Brown Sequard publicized “organotherapy”, which was initially carried out with testicular extracts. Other animal glands such as the thyroid, adrenal, and pancreas, were also used, with varying degrees of success, to treat hormone deficiency.

Improvements in chemistry, pharmacy, and allied sciences led to innovations in endocrine pharmacology. Researchers began using a variety of compounds, both natural and synthetic, to treat endocrinopathy. By the mid-20th century, treatments were available for pituitary, thyroid, parathyroid, pancreatic, adrenal, and gonadal disease. As our understanding of the pathophysiological basis of metabolic and hormonal disease improved, newer drugs were invented on purpose, rather than discovered by chance.

The late decades of the century witnessed a rapid spirit in new drug development, especially in the fields of diabetes and metabolism. Unfortunately, many of these “new” drugs had to be withdrawn from the market, due to safety and tolerability issues. In bariatrics, ephedrine, fenfluramine, phenteramine, riminabant, and sibutramine, all bit the dust, one by one. In diabetes, the earlier sulfonylureas (tolbutamide, chlorpropamide), phenformin, troglitazone, and rosiglitazone were withdrawn.

An enhanced, though belated, realization of the importance of safety and tolerability of drugs, along with efficacy, lead to a tightening of norms related to newer drug approval. This phenomenon has been a major feature of endocrine pharmaceutic development during the first decade of the 21st century. In spite of innovations in combinatorial chemistry, sequencing of the human genome, automation in screening of drug libraries, and advances in molecular biology and genetics, the productivity of drug inventors is declining. Because of the limitations and curbs imposed by regulatory authorities, the rate of approval of endocrine drugs may go down. The peak of 11 metabolism- and endocrinology-related drugs approved by the FDA was in 2010 and it seems difficult to be able to match this in future.

With this background in mind, one can understand the importance of exaptation in endocrine pharmacology.

Endocrine pharmacology has multiple examples of exaptation. Endocrine or metabolic drugs have been exapted for nonendocrine diseases, as well as nonhormonal drugs have been exapted for diagnostic use in endocrinology. A novel phenomenon, namely xeno-exaptation has been noted wherein human hormones are exapted for botanical use. This will be discussed later in this editorial.

Endocrine drugs like metformin, originally developed for the management of diabetes, has been exapted (though off-label) for use in polycystic ovarian syndrome. Liraglutide and exenatide, used as antidiabetic drugs, seem to hold more promise as antiobesity drugs. Exaptation of endocrine drugs also extends beyond endocrinology. The recently developed class of gliptins is being explored as potential therapy in immune-mediated diseases such as Crohn's disease and rheumatoid arthritis, as well as cancer. DHEA-S is accepted for use in systemic lupus erythematosis.

Nonendocrine drugs have been exapted for use in endocrinology, too. Clonidine, originally used as a nasal decongestant, has been exapted for multiple uses in endocrinopathies, including hot flashes and diabetic autonomic neuropathy. Similarly, bromocriptine has experienced multiple exaptations, from use in Parkinson's disease to hyperprolactinemia and diabetes. Minoxidil, originally developed as an antihypertensive, is utilized in androgenetic alopecia. While the therapeutic advantages of such exaptations are well known, the diagnostic uses of these pharmacologic agents often escape notice. Numerous drugs are used in stimulation and suppression tests designed to diagnose hormonal diseases. Examples include the use of insulin and clonidine to help diagnose growth hormone deficiency.

The phenomenon of endocrine exaptation extends far beyond human diagnostics and therapeutics, however. Enterprising farmers in north India have pioneered a drug use which can only be termed as endocrine xenoexaptation. Oxytocin, a full-blooded mammalian hormone is used in injectable form to increase crop yields of pumpkins and cucumbers. This hormone has also been used to enhance milk yield in lactating cows and buffaloes. This represents a reverse xenobiotic usage, from humans to other plant or animal species, instead of vice versa. A mammalian pituitary hormone, with multiple actions, which has already been exapted to augment labor and manage postpartum hemorrhage, in humans, is now being xenoadapted to improve reproductive yield in plants. The efficacy of this endocrine experiment is beyond the scope of this editorial.

Apart from this, however, exaptation is serious science. Confronted with an epidemic of metabolic and endocrine disease and faced with the prospect of fewer and fewer new drugs reaching the market, endocrinologists need to explore existing drugs with proven safety for their pleiotropic effects.

The concept of exaptation, proposed by evolutionary biologists, should be exapted to endocrine pharmacology.

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