The Chronobiology of Hormone Administration: "Doctor, What Time Should I Take My Medication?"

Abstract

Pharmacotherapy involving hormones and hormone-derived molecules has various potential treatment targets. This includes addressing (partial) hormonal deficiencies, pursuing osteoanabolic effects, providing contraceptive options, or supporting gender-affirming transitions. In chronotherapy, the timing of the administration of active ingredients and different pharmaceutical forms is leveraged to maximize therapeutic efficacy while minimizing adverse effects, based on the principle that it is optimal for drugs to be administered according to the body's circadian rhythms. Just as a drummer sets the pace and keeps the rhythm steady for the entire band, the physician, through the application of chronotherapy, ensures the treatment regimen is harmonized with the body's internal clock. However, while this is a consolidated aspect for several endocrine treatments, for others, it represents a novelty. The new advancements in the treatment of osteoporosis, with the latest parathyroid hormone-related protein analogue, abaloparatide, or in congenital adrenal hyperplasia with the new long-lasting hydrocortisone formulation, are notable examples. We herein summarized the state of the art regarding the hormonal circadian rhythm to discuss in depth the evidence available regarding the correct timing of commonly administered hormonal therapies in adult patients. By offering clear indications, this manuscript delves into the importance of harmonizing hormonal therapy with circadian rhythms through chronotherapy, exploring its potential to enhance therapeutic outcomes while minimizing adverse effects.

Keywords: chronobiology; chronotypes; circadian rhythm; glucocorticoids; hormone replacement; pharmacotherapy.

Graphical Abstract

Figure 1.

(A) Diurnal rhythm of thyroid-stimulating hormone (TSH), parathyroid hormone (PTH), cortisol, growth hormone (GH), antidiuretic hormone (ADH), estradiol, testosterone, insulin, glucagon-like peptide 1, and leptin. (B) Timing of hormone administration, including levothyroxine, recombinant human parathyroid hormone (rhPTH), hydrocortisone, cortisone acetate, modified-release hydrocortisone, fludrocortisone, recombinant human growth hormone (rhGH), desmopressin, testosterone, estrogen, progesterone, estroprogestinics, rapid-acting insulin, long-acting insulin, liraglutide, exenatide, oral semaglutide, and metreleptin. Legend: Solid ✓ indicates recommended administration, dashed ✓ indicates alternative administration, and dotted ✓ indicates additional administration. Timing of hormone administration is indicative; treatment should be personalized based on the patient's wake/sleep schedule and chronotype for optimal efficacy. *Bedtime administration of the modified-release hydrocortisone applies only to congenital adrenal hyperplasia (CAH). Created in BioRender (https://BioRender.com/j78z959).

Figure 2.

The hypothalamic-pituitary-adrenal (HPA) axis is regulated by the master circadian clock in the suprachiasmatic nucleus (SCN), which synchronizes with light signals via the retino-hypothalamic tract. The SCN influences the paraventricular nucleus (PVN) to release CRH and AVP, stimulating ACTH secretion from the pituitary and driving glucocorticoid production in the adrenal gland. Local adrenal clocks also modulate ACTH responsiveness. Glucocorticoid levels peak before the active phase, and stress signals further activate the HPA axis via inputs to the PVN. Inset: The molecular circadian clock involves a transcriptional-translational feedback loop (TTL) of CLOCK/NPAS2, BMAL1, PERs, and CRYs, cycling over 24 hours. Created in BioRender (https://BioRender.com/s51x907).