Revisiting the role of steroidal therapeutics in the 21st century: an update on FDA approved steroidal drugs (2000–2024)

Abstract

Steroids are biologically active polycyclic compounds that have garnered significant scientific attention due to their distinct physiochemical properties and diverse medical applications. Since their invention more than 90 years ago, steroids have remained the most important and necessary class of regulatory molecules in the evolution process of living creatures and have fascinated scientists due to their broad-spectrum biological activities. Over time, scientific innovations and expanded understanding of mechanisms related to diversified biological activities of steroids have made them cheaper, efficient and more specific therapeutic agents which could be effective in the prevention and cure of numerous diseases like cancer, inflammation, asthma, microbial infection, and many more. However, steroidal drugs remain a double-edged sword having significant therapeutic benefits but with incidence of several adverse effects if used for a longer duration and/or with incorrect dose. Nevertheless, novel treatment approaches such as nanoparticles or liposomal drug delivery, real-time monitoring and the use of artificial intelligence in steroidal therapy outweigh their risk factors and provide an effective and safe treatment with minimum adverse effects. Furthermore, the repurposing of steroids in different diseases, e.g. successful use of dexamethasone or hydrocortisone during COVID-19 pandemic has renewed the interest in steroidal therapeutics. The present review provides an update on FDA approved steroidal drugs during the years 2000–2024, the status of their clinical studies, the challenges offered by steroidal therapy and the future perspectives to counterbalance all these challenges. Moreover, this review also delivers useful data on the repurposing of steroidal drugs against various diseases along with the novel techniques used for improved steroid delivery.

The present review article provides information about the steroidal drugs approved by the US FDA during the years 2000–2024 and repurposing of steroidal drugs for various disorders in the 21st century.

1. Introduction

1.1. Evolution of steroids – from a chemical entity to potential medicinal candidates

Steroids comprise a group of biologically active polycyclic compounds consisting of four fused rings arranged as three cyclohexane rings (A, B, and C) and one cyclopentane ring (D) called sterane (cyclopentanoperhydrophenanthrene) as shown in Fig. 1. Steroids are lipophilic low-molecular weight compounds, which are biosynthesized from cholesterol (Fig. 1) and also obtained from a variety of marine and terrestrial sources.^1,2 The steroid family includes sterols (cholesterol), hormones (both gonadal and adrenal cortex), bile acids and their metabolites. All these play an important role in the physiological and biochemical functioning of living organisms.³

Fig. 1. Chemical structures of sterane and cholesterol.

In the 18th century, the first use of steroids was made for the treatment of dropsy (edema), a condition characterized by the accumulation of fluid in soft tissues and linked with heart failure, by English physician William Withering using digitalis, a compound extracted from the leaves of foxglove (Digitalis purpurea).⁴ In the early 19th century, chemists commenced studies on cholesterol and a few acids isolated from animal fat, gallstones and bile. The complex polycyclic structure of the steroid nucleus was identified at the beginning of the 20th century due to the progress in chemical and spectral techniques.^1,2,5 Adolf Windaus, a German chemist also referred to as the “Father of Steroid Chemistry” carried out arduous studies with the help of his research group and finally proved the structures of cholesterol and some related sterols such as stigmasterol and ergosterol and won Nobel prize in chemistry in 1928.⁶ As the fundamentals of steroid chemistry were unravelled, it began an era of structure elucidation and exploration of the physiological potential of steroid hormones of gonads and adrenal cortex. A Nobel Prize in Physiology or Medicine in 1950 to American scientists Philip S. Hench and Edward C. Kendall for the discovery of cortisone, an adrenal hormone effective in rheumatoid arthritis, further stimulated steroid research.⁷ With the passage of time, the biochemistry of steroids was better understood and further with the assistance of new analytical and radio-isotopic techniques, it became easy to study the metabolic pathways (both synthesis and decomposition) and their pharmacological mechanisms. In the later part of the 20th century, novel routes of synthesis of steroidal derivatives were developed and various new analogues were therapeutically evaluated and then extensively explored for cancer, inflammation, asthma, osteoporosis, and cardiovascular diseases, and as contraceptives. All these developments galvanize the steroidal research and development programmes in pharmaceutical industries which further expanded the fundamental knowledge regarding their chemical structures and medical applications.^8–11 Collectively, the versatile features of steroid-derived compounds made them potential drug candidates for the treatment of various diseases.

1.2. Therapeutic role of steroids in healthcare

Steroids are not only man-made but are also found naturally in the human body as i) sex hormones including androgens, estrogens, and progestogens responsible for sex differentiation and reproduction, ii) corticosteroids like glucocorticoids (regulate metabolic and immune function) and mineralocorticoids (maintain blood volume and electrolytes levels) and iii) anabolic steroids which help in gaining muscle mass and promote bone synthesis (Fig. 2).^12,13

Fig. 2. Classification and general functions of steroids.

Steroids are of great importance in the medical field for treating numerous diseases and as performance enhancing agents. Some of the typical examples include SAIDs (steroidal anti-inflammatory drugs) in the form of tablets and capsules for control of inflammation, injections to get relief from joint and ligament pains and inhalers in the therapy of asthma. Further, steroidal creams/lotions/gels/ointments, tapes and bandages are used in skin conditions such as eczema. Steroidal derivatives have already proven their therapeutic potential in curing cancer, e.g. brain tumors effectively respond to steroidal drugs as they relieve the pressure in the swollen brain. In addition, oral and injectable anabolic steroids are used to build muscle tissue and increase body mass as they act like the natural male hormone, testosterone. This helps not only the patients to gain weight after a severe illness, injury, or continuing infection but also athletes and weightlifters in sports.^12–15 The detailed aspects of therapeutic applications of steroids have been provided in Table 1.^12–28

Table 1. Therapeutic applications of steroids in healthcare^12–28.

Disease/condition	Steroids	Mode of action	Therapeutic applications
Inflammation	Short acting	Inhibit phospholipase A2 and decrease the production of inflammatory mediators	Rheumatoid arthritis, myositis and gout
	Hydrocortisone and cortisone		Lupus
	Intermediate acting		Uveitis
	Prednisone, prednisolone, methylprednisolone and triamcinolone		Inflammatory bowel disease (IBD) including ulcerative colitis and Crohn's disease
	Long acting		Systemic vasculitis
	Betamethasone, dexamethasone, and paramethasone		Autoimmune hepatitis
	Topically acting
	Beclomethasone dipropionate, budesonide, fluocinolone acetonide and fluocortolone
Respiratory disorders	Inhaled corticosteroids	Inhibit the release of leukotrienes (LT) mainly LT-C4 and LT-D4. This helps in reducing bronchial mucus secretion, reducing bronchial hyperreactivity and modifying the bronchial response to bronchoconstrictor	Asthma
	Fluticasone	Enhance beta-adrenergic response to relieve the muscle spasm	Chronic obstructive pulmonary disease (COPD)
	Budesonide		Exercise-induced bronchoconstriction (EIB)
	Mometasone		Sarcoidosis
	Beclomethasone		Pneumonitis
	Systemic steroids for asthma		Interstitial lung disease
	Dexamethasone
	Methylprednisolone
	Prednisone
	Prednisolone
Cardiovascular disorders	Cardenolides	Inhibit sodium-potassium ATPase pump to strengthen the heart and regulate heart rate	Congestive heart failure
	Digoxin	Diuretic	Myocardial infarction
	Digitoxin		Tachyarrhythmia
	Ouabain		Hypertension and heart failure
	Rostafuroxin
	Bufadienolides
	Marinobufagenin proscillaridin A
	Spironolactone
	Eplerenone
Cancer	Prednisolone	Steroids not only destroy and shrink tumors but also have multiple roles in cancer therapy. They prevent allergic reactions due to blood product transfusion or medication, control chemotherapy-induced nausea and vomiting, and reduce pain and inflammation during cancer treatment	Leukemia
	Methylprednisolone		Lymphoma
	Dexamethasone		Myeloma
	Hydrocortisone		Solid tumors (cancers of the lung, breast, prostate, colon and rectum)
	Prednisone
	Bendamustine
	Exemestane
	Finasteride
Dermatological disorders	Mild corticosteroids	Decrease epidermal mitosis and increase lipocortin which is useful in the treatment of psoriasis	Eczema
	Clobetasone	Immunosuppressive effects	Contact dermatitis
	Hydrocortisone		Psoriasis
	Strong corticosteroids		Urticaria or hives
	Beclometasone
	Betamethasone
	Clobetasol
	Fluticasone
	Mometasone
Endocrine disorders	Cortisone	Regulate steroidogenesis	Addison's disease
	Hydrocortisone		Congenital adrenal hyperplasia
	Desoxycorticosterone acetate
	Prednisolone
	Prednisone
Miscellaneous disorders
Allergy	Steroidal nasal sprays	Anti-inflammatory effect	Sinusitis
	Beclomethasone		Allergic and non-allergic rhinitis
	Budesonide
	Fluticasone
	Mometasone
Contraceptives	17-Acetoxy progestogens	Suppress the release of gonadotropin	Contraceptives
	Medroxyprogesterone acetate
	Chlormadinone acetate
	Megestrol acetate
	Levonorgestrel
	Norethindrone
	Norgestimate
	Ethinyl estradiol
Appearance and performance enhancing drugs (APEDs)	Testosterone	Promote the growth of skeletal muscle by increasing the production of red blood cells (anabolic effects) in both males and females	Muscle dysmorphia
	Nandrolone		To treat delayed puberty in adolescent boys, hypogonadism and impotence in men
	Oxandrolone		To treat anaemia, osteoporosis and hormonal imbalance in females
	Oxymetholone
	Stanozolol
	Trenbolone acetate
Organ transplantation	Prednisolone	Immunosuppression	Kidney transplant
	Methylprednisolone		Liver transplant
	Dexamethasone		Heart transplant
	Hydrocortisone		Lung transplant

2. Present scenario of steroidal drugs

In the last 50 years, several novel steroidal derivatives with diverse biological effects have been invented and developed. Currently, their therapeutic effects are well established with the recognized mechanism of action against numerous disorders. In the last two decades, the Food and Drug Administration (FDA) has approved several steroidal drugs for the treatment of various health related disorders. Many steroidal molecules having distinct chemical structures are undergoing clinical trials for cancer, COVID-19, hormonal replacement therapy and many more.^14,15,29,30

2.1. Outline of FDA approved steroidal drugs (2000 to 2024)

The US FDA approved as many as 1410 New Molecular Entities (NMEs) during the years 2000 to 2024 (Table 2 and Fig. 3). Of them, fifty four (53) novel molecular entities are steroidal in nature and have been approved for the therapy of various diseases such as asthma, cancer, inflammation, menopause symptoms, dermatological problems and neurodegenerative disorders (Table 2). In the first decade of the 21st century, thirty six (36) steroidal drugs were approved by the US-FDA as anti-inflammatory, anti-asthmatic, anti-cancer and contraceptive agents. After the year 2010, the FDA further extended the therapeutic potential of steroidal drugs and approved nineteen (17) such molecules for the treatment of postpartum depression, chronic liver diseases, menopause problems, breast cancer and muscular dystrophy. In the current decade, the FDA approved two steroidal drugs with brand names Relyvrio® and Ztalmy® as neuroprotective agents for the treatment of amyotrophic lateral sclerosis and epilepsy, respectively, in the year 2022.³¹

Table 2. Year-wise list of steroidal drugs approved by the FDA (2000–2024)³¹.

Year of drug approval	Active pharmaceutical ingredient	Therapeutic use
	(Brand name)
2024	—	—
2023	Vamorolone	Duchenne muscular dystrophy
	(Agamree)
	Zuranolone	Postpartum depression
	(Zurzuvae)
	Omaveloxolone	Friedrich's ataxia
	(Skyclarys)
2022	Taurursodiol/sodium phenylbutyrate	Amyotrophic lateral sclerosis (ALS)
	(Relyvrio)
	Ganaxolone	Epilepsy or seizures
	(Ztalmy)
2021	Drospirenone/estetrol	Contraceptive
	(Nextstellis)
2020	Fluoroestradiol F18	Diagnostic imaging agent for certain patients with breast cancer
	(Cerianna)
	Clascoterone	Acne
	(Winlevi)
2019	Brexanolone	Postpartum depression
	(Zulresso)
2018	Segesterone acetate/ethinyl estradiol	Contraceptive
	(Annovera)
2017	Deflazacort	Duchenne muscular dystrophy (DMD)
	(Emflaza)
2016	Obeticholic acid	Rare chronic liver diseases such as acute hepatic porphyria (AHP) and autoimmune hepatitis (AIH)
	(Ocaliva)
2015	Cholic acid	Bile acid synthesis disorders (BASDs)
	(Cholbam)
	Deoxycholic acid	Improve the appearance and profile of moderate to severe fat below the chin (submental fat)
	(Kybella)
2013	Fluticasone furoate	Chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema
	(Breo ellipta)
	Estrone sulfate (sodium)/bazedoxifene	Moderate-to-severe hot flashes
	(Duavee)
2011	Abiraterone acetate	Combination with prednisone to treat prostate cancer
	(Zytiga)
2010	Ulipristal	An emergency contraceptive pill
	(Ella)
	Estradiol valerate/dienogest	Contraceptive
	(Natazia)
2009	Flunisolide	Allergic rhinitis
	(Aerospan)
	Levonorgestrel	Contraceptive
	(Skyla)
2008	Calcipotriene/betamethasone dipropionate	Psoriasis vulgaris
	(Taclonex)
	Triamcinolone acetonide	Uveitis and ocular inflammatory conditions
	(Trivaris)
	Difluprednate	Treatment of eye swelling and pain after eye surgery
	(Durezol)
	Equilin sodium sulfate	Symptoms of menopause such as hot flashes, vaginal dryness
	(Cenestin)
2007	Drospirenone/ethinyl estradiol	Oral contraceptive, premenstrual dysphoric disorder (PMDD) and acne
	(Yaz)
	Clobetasol propionate	Eczema and psoriasis
	(Olux E)
	Fluticasone furoate	Allergic and non-allergic nasal conditions like rhinitis
	(Veramyst)
	Ethinylestradiol/levonorgestrel	Contraceptive
	(Lybrel)
	Hydrocortisone butyrate	Eczema, dermatitis, allergies and rash
	(Locoid)
2006	Ciclesonide	Asthma in adults and children aged 12 years or older
	(Omnaris)
	Fluticasone propionate	Eczema and psoriasis
	(Advair HFA)
	Prednisolone sodium phosphate	Arthritis, blood and immune disorders, skin and eye problems, breathing issues, cancer, and severe allergies
	(Orapred ODT)
	Budesonide	Difficulty breathing, chest tightness, wheezing, and coughing caused by asthma
	(Pulmicort flexhaler)
	Etonogestrel	Contraceptive
	(Implanon)
	Desonide	Eczema, dermatitis, allergies and skin rashes
	(Verdeso)
	Ciclesonide	Asthma and allergic rhinitis
	(Omnaris)
2005	Fluocinonide	Treatment of skin disorders such as eczema and seborrheic dermatitis
	(Vanos)
2004	Fluocinolone acetonide	Eczema, dermatitis, allergies, rash
	(Retisert)
	Clobetasol propionate	Skin inflammation and itching
	(Clobex)
2003	Medroxyprogesterone acetate	Symptoms of menopause (such as hot flashes, vaginal dryness)
	(Prempro/Premphase)
	Estradiol hemihydrate	Contraceptive
	(Estrasorb)
2002	Eplerenone	Hypertension and congestive heart failure (CHF)
	(Eplerenone)
	Fulvestrant	Metastatic breast cancer
	(Faslodex)
2001	Dutasteride	Benign prostatic hyperplasia
	(Avodart)
	Norelgestromin/ethinyl estradiol	Contraceptive
	(Ortho Evra)
	Cortisone acetate	Allergic disorders, skin conditions, ulcerative colitis, arthritis, lupus, psoriasis, and breathing disorders
	(Cortone)
	Norethindrone acetate	Menopause symptoms such as hot flashes and vaginal changes
	(Activella)
2000	Fluticasone propionate	Inflammation
	(Advair Diskus 500/50)
	Beclomethasone dipropionate	Psoriasis, eczema, dermatitis, allergies, rash
	(Qvar 80)
	Estradiol cypionate	Menopausal symptoms
	(Lunelle)
	Betamethasone dipropionate/clotrimazole	Fungal infections of the feet, groin, and body in people aged 17 years or older
	(Lotrisone)
	Desogestrel/ethinyl estradiol	Combination hormone medication to prevent pregnancy
	(Cyclessa)

Fig. 3. Chemical structures of steroidal drugs approved by the FDA (2000–2024).

The year-wise percentage of steroidal drugs in comparison to overall approved drug molecules by the FDA has been shown in Table 3.³¹

Table 3. Year-wise comparative percentage of steroidal drugs approved by the FDA (2000–2024) for various diseases.

Year	Number of FDA approved drugs	Number of steroidal drugs approved by FDA	Percentage of steroidal drugs	Targeted disease
2023	55	3	5.4%	Neurodegenerative disorders
2022	37	2	5.4%	Amyotrophic lateral sclerosis, epilepsy
2021	50	1	2%	Contraception
2020	53	2	3.7%	Acne, breast cancer
2019	48	1	2.08%	Postpartum depression (PPD)
2018	59	1	1.69%	Contraception
2017	46	1	2.17%	Duchenne muscular dystrophy (DMD)
2016	22	1	4.5%	Acute hepatic porphyria (AHP), autoimmune hepatitis (AIH)
2015	45	2	4.44%	Fat burner
				Bile acid synthesis disorders
2014	41	0	0	NA
2013	27	2	7.4%	Menopause problem
				Chronic obstructive pulmonary disease (COPD)
2012	39	0	0	NA
2011	30	1	3.33%	Cancer
2010	21	2	9.52%	Contraception
2009	25	2	8.0%	Psoriasis
				Contraceptives
2008	93	4	4.3%	Inflammation
				Dermatological problems
				Contraception
				Cure menopause hot flashes and vaginal dryness
2007	88	5	5.68%	Asthma,
				Contraception
				Allergic and non-allergic nasal symptoms
				Eye swelling and pain
				Skin conditions such as psoriasis, eczema, dermatitis
2006	112	7	6.25%	Psoriasis, eczema and dermatitis
				Asthma
				Cure menopause symptoms, contraception
				Allergic and non-allergic nasal symptoms
2005	82	1	1.21%	Psoriasis, eczema, dermatitis
				Allergies and rash
2004	105	2	1.92%	Psoriasis, eczema, dermatitis
				Allergies and rash
2003	78	2	2.56%	Cure menopause symptoms, psoriasis, eczema, dermatitis
				Allergies and rash
2002	89	2	2.24%	Hypertension, congestive heart failure (CHF)
				Metastatic breast cancer
2001	66	4	6.06%	Benign prostatic hyperplasia
				Contraception
				Inflammation
				Cure menopause hot flashes and vaginal dryness
2000	99	5	5.05%	Fungal infections
				Contraception
				Psoriasis, eczema, dermatitis
				Allergies and rash
				Allergic and non-allergic nasal symptoms
Total	1410	53

2.2. Steroidal drug candidates undergoing clinical trials

It is well known that steroids affect almost every organ of the biological system, hence there is an increasing demand for new steroid based molecules for various clinical purposes. Accordingly, numerous pharmaceutical industries have shown their keen interest in the research and development in this area.¹⁵ At present, several steroidal drug candidates are in various phases of clinical trials for cancer, inflammation, asthma, psoriasis, neurodegenerative disorders and cardiovascular diseases. The current status of clinical studies on different steroidal drug candidates along with the targeted disease has been presented in Table 4 and their structures are given in Fig. 4.

Table 4. Current status of steroidal drug candidates undergoing clinical studies for various disorders.

S. no	Steroid	Targeted disorder	Clinical phase	Ref.
1.	GW870086X	Inflammation	Phase 1/NCT00549497	32
2.	Vamorolone	Duchenne muscular dystrophy (DMD)	Phase 2/NCT03439670	33
3.	TAS-108	Breast cancer	Phase 2/NCT00166543	34
4.	Halobetasol propionate	Plaque psoriasis	Phase 2/NCT01610596	35
5.	Danazol	Severe hematologic or pulmonary disease	Phase 2/NCT03710356	36
6.	Mometasone furoate	Asthma	Phase 2/NCT02741271	37
7.	PGL2001	Endometriosis	Phase 2/NCT01631981	38
8.	Dexamethasone 21-phosphate	Ulcerative colitis	Phase 2/NCT01171807	39
9.	Galeterone	Metastatic pancreatic adenocarcinoma	Phase 2/NCT04098081	40
10	Digoxin	Medulloblastoma	Phase 2/NCT06701812	41
11.	Larsucosterol (DUR-928)	Alcoholic hepatitis	Phase 2/NCT04563026	42
12.	Spironolactone	Persistent facial acne	ISRCTN12892056 and EudraCT (2018-003630-33)	43
13.	Exemestane	Breast cancer in postmenopausal women	Phase 3/NCT00083174	44
14.	Fluorometholone	Adjunctive medical therapy for trachomatous trichiasis (TT) surgery	Phase 3/NCT04149210	45
15.	Potassium canrenoate	Sinus rhythm restoration among patients with atrial fibrillation	Phase 4/NCT03536806	46
16.	Mifepristone	Medically induced abortions	Phase 4/NCT00269568	47
17.	Nerium oleander	Immune function	Phase (NA)/NCT04486144	48

Fig. 4. Chemical structures of steroidal drugs undergoing clinical trials for various diseases.^32–48.

3. Drug repurposing – rekindled interest towards steroidal therapeutics

Steroidal drugs have been successfully repurposed for various disease conditions in the 21st century rekindling the interest of scientists towards steroidal therapeutics.⁴⁹ The majority of the steroidal drugs repurposed during this period belong to the class of corticosteroids. On the other hand repurposing of sex steroids as neuroprotective agents and several other steroids for various miscellaneous purposes are also being considered.

3.1. Corticosteroids for COVID-19: rescue in pandemic

Coronavirus disease 19 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The World Health Organization (WHO) declared COVID-19 as a global pandemic in March 2020. The WHO primarily recommended corticosteroids, in particular, dexamethasone as the first line of drug or essential medicine for the treatment of patients with severe COVID-19. Prednisone, methylprednisolone and hydrocortisone (Fig. 5A) are also used alone or in combination therapy for treating mild, moderate and critically infected COVID-19 patients. The drugs are easily accessible worldwide at economical prices in multiple formulations and various dosage forms.⁵⁰ Corticosteroids act by regulating immune response and minimize the duration of hospitalization for seriously ill patients. Recently, it has been reported that corticosteroids may possess a stimulatory as well as inhibitory action on the immune system depending upon their duration of action and blood concentration.⁵⁰ This provides much needed support to the patients whose lungs are damaged due to inflammation and fluid accumulation in the severe incidents of COVID-19. Ultimately this reduces the time spent on a mechanical ventilator, residing period in an intensive care unit (ICU) and most importantly the death rates of COVID-19 patients.^51–53

Fig. 5. Chemical structures of repurposed steroidal drugs.

During a controlled trial study on COVID-19 patients in March 2020, dexamethasone decreased the mortality rate by 33% in patients on ventilators and 20% in patients who received oxygen therapy.⁵⁰ Dexamethasone therapy of short duration at recommended doses produced no serious side effects except a temporary condition of high blood glucose levels (hyperglycaemia).^50,54 Methylprednisolone is another corticosteroid which reduced the mortality rates and has shown promising results in critically ill COVID-19 patients.^50,55 Hydrocortisone and prednisone offered similar life-saving benefits in COVID-19 patients and are used in patients suffering from pneumonia and hypoxia to reduce the risk of death.^50,56,57 Combination therapy of corticosteroids with drugs like remdesivir, tocilizumab and baricitinib is very useful in treating COVID-19 infection. A combination of dexamethasone plus remdesivir or dexamethasone plus tocilizumab is used to treat hospitalized patients requiring an increasing amount of supplemental oxygen or high-flow oxygen or those having significantly increased proinflammatory markers such as interleukin-6 (IL-6), interleukin-10 (IL-10) and interferon-gamma (IFN-γ). Dexamethasone and baricitinib combination is used in selected patients, who are on low-flow oxygen but need higher levels of respiratory support due to inflammation in lungs.⁵⁰

Though corticosteroids are part of the WHO model list of essential medicines they should be used under clinical supervision for the treatment of COVID-19 patients. The use of corticosteroids in the treatment of COVID-19 treatment is controversial as some scientific reports are against corticosteroid treatment due to their side effects such as obstructed clearance of viral RNA from the respiratory tract and blood, psychosis, induced diabetes, lung injury or shock. On the other hand, many scientific reports support the use of corticosteroids in low-to-average amounts for a shorter period as it decreases the death rate and minimizes the duration of hospitalization for seriously ill COVID-19 patients without causing much serious side effects. Intensive research on corticosteroid therapy in COVID-19 treatment is urgently needed to elucidate their mechanisms and importance in contributing toward successful prevention and treatment approaches.^50,57,58

3.2. Neuroprotective potential of steroidal drugs

Both natural and synthetic steroids physiologically regulate and protect the central and peripheral nervous system from neurodegeneration, hence termed as “neuroprotective or neuroactive”. Steroids are highly lipophilic molecules, hence they easily cross the blood–brain barrier (BBB) and exert their neuroprotective actions through steroid hormone receptors localized within cells and blood vessels of the brain. Neuroprotective steroids shield the neurons mainly from neuroinflammation, oxidative and excitotoxic stress, the factors implicated in neuronal cell death, and stimulate neurotransmission and various repair processes, e.g., neurogenesis, myelination, and expression of antiapoptotic factors. Further, reduction in reactive gliosis and proinflammatory cytokines (TNF-α, IL-1β, and IL-6) results in reduced edema in an injured brain. Natural steroids such as 17β-estradiol, dehydroepiandrosterone (DHEA), testosterone, and progesterone (Fig. 5B) and synthetic ones, e.g., dexamethasone, prednisolone, methylprednisolone, hydrocortisone, promote neuronal survival through several mechanisms in the CNS.^11,59,60

17β-Estradiol, a female sex hormone, plays a crucial role in the regulation of cholinergic neurotransmission and promotes synaptic transmission and neuronal survival. It suppresses chemokine-mediated induction of the cyclooxygenase-2 (COX-2) pathway in cerebral blood vessels, and hence reduces neuroinflammatory cytokines like TNF-α, IFN-γ, and IL6 and increases the anti-inflammatory transforming growth factors (TGF) β2 and β3. Estradiol controls the hyperphosphorylation of tau protein and regulates β-amyloid accumulation in patients of AD, while in the case of PD and MS, it regulates the expression of myelin protein and thus increases the release of growth factors such as BDNF and IGF-1 and also exerts neuroprotective effects by enhancing the ratio of antiapoptotic Bcl-2 proteins.^11,59,60

DHEA, an endogenous steroid, enters into the brain from circulation but its small amount is also produced locally in the brain. It easily gets converted to neuroprotective steroids testosterone, dihydrotestosterone or estradiol in the brain. DHEA produces antioxidant, anti-neuroinflammatory (suppress IL-1β, TNF-α, and IL-6 expressions) and antiapoptotic effects and also stimulates neurogenesis in an injured brain. DHEA showed promising results in preclinical studies for AD and PD by improving the cognitive and locomotor functions. A combination of DHEA and low dose L-DOPA produced noteworthy anti-Parkinsonian effects by inhibiting dopamine degeneration in the brains of female monkeys treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).^61,62 Several clinical studies support the use of DHEA in preventing the gradual accumulation of toxic Aβ proteins in AD patients by impeding the processing of amyloid-beta precursor protein (APP).^11,62

Testosterone produces neuroprotective effects either by regulating the activity of the neuronal cells by directly acting through the androgen pathway or indirectly by conversion into estrogens. Testosterone protects the nerve cells from oxidative stress, neuroinflammation, and apoptosis and enhances the neuronal size, plasticity, neurite growth, and synaptogenesis in the spinal trigeminal nucleus in AD, PD and MS patients. The reduced levels of testosterone on ageing lead to impaired cognitive function, hence its supplements in aged patients produce the favourable effects. Like DHEA, inhibition of NMDA excitotoxicity and upregulation of nerve growth factor (NGF) levels have been observed in several preclinical studies using testosterone in PD while overexpression of amyloid β and inhibition of the hyperphosphorylation of tau proteins were seen in the case of AD. Further, testosterone therapy significantly improved the density as well as reduced the loss of gray matter in the brain of patients suffering from MS in experimental studies.^11,63 Inhibition of neuronal death and edema, improved functional recovery in patients by downregulating the inflammatory cascade (decelerating IL-1β, IL-6, TNF-α induced reactions), reduced oxidative stress via upregulation of antioxidant enzymes, decreased excitotoxicity by inhibition of glutamate receptors and inhibition of glial cell activation in the CNS are seen with progesterone therapy. Treatment with progesterone derivatives like allopregnanolone and pregnenolone improves cognitive functions and reduces hyperphosphorylation of tau proteins in AD. Studies have shown prevention of apoptotic cell death in human NT2 cell cultures in NMDA-induced excitotoxicity and stabilization of microtubules by improved polymerization, enhanced myelination and activated NGF with progesterone treatment.^11,64

Synthetic glucocorticoids, especially dexamethasone, prednisolone, methyl-prednisolone, and hydrocortisone, exhibit neuroprotective effects by tackling neuroinflammation (reducing the release and expression of proinflammatory cytokines TNF-α, IL-1β, and IL-6) and by preventing oxidative stress (enhancing the antioxidative capacity and diminishing lipid peroxidation, free radical generation) in the brain. Hence, they are used alone or in combination with other drugs for the therapeutic management of various neurological disorders.^11,65–68 Overall, natural and synthetic steroids maintain homeostasis within the brain and promote neuroprotection. Extensive structural exploration of all these steroids could lead to the development of potential molecules for the prevention of neurodegeneration.

3.3. Steroids in infectious diseases

In recent years, the advancements in the field of antimicrobials to overcome drug resistance associated with microbes are of much interest for the scientific community. In the last few decades, the rational modifications within the steroid nucleus have generated molecules capable of combating multi-drug resistance, and their high bioavailability help in penetrating the cell wall of infectious agents. In this way, steroidal drugs have played a significant role against bacterial, viral, fungal, and parasitic infections.⁶⁹

A clinical trial of adjunctive steroid therapy revealed that early treatment with dexamethasone improves the outcome in patients with pneumococcal meningitis. The decreased mortality rate, neurological sequelae and absence of adverse effects with short-term steroid therapy boosted confidence in beneficial use of such therapy in meningitis patients.⁷⁰Acne fulminans or acne maligna is a rare form of acne appearing on the face, upper chest and back and is characterized by an abrupt onset of painful, inflammatory and ulcerative lesions covered with haemorrhagic crusts. Another case report of use of combination of oral prednisolone with antimicrobial agents (clindamycin) outlined it as a promising regime for the treatment as well as prevention/progression of the disease.⁷¹ Currently, dexamethasone is the only clinically approved adjunctive chemotherapeutics for tuberculosis (TB) having advantageous effects on survival of TB patients, although the exact mechanism of action is still unclear. However, inhibition of necrotic death of cells infected with Mycobacterium tuberculosis and suppression of TNFα in hyper-inflammatory states of the disease are assumed to be the possible mechanisms.⁷²

Steroid–polyamine conjugates are very effective against Gram-positive and Gram-negative bacteria, fungi, and protozoa as they bind to the DNA of these microorganisms and inhibit their growth. An aminosterol conjugate of dexamethasone and spermine has been reported to have bactericidal effects on S. aureus and P. aeruginosa. It has been observed that the conjugate prevents inflammation involving proinflammatory molecules like interleukin-6 (IL-6), lipopolysaccharide (LPS), and IL-8 and could be useful as a therapeutic remedy against bacterial infections and related inflammation.^73,74 A pregnenolone–carbamazepine conjugate displayed minimum inhibitory concentration (MIC) against Proteus mirabilis comparable to cefotaxime, gentamicin, and ciprofloxacin,⁷⁵ whereas the pregnenolone–danazol conjugate caused disruption of the cell membrane of bacteria like S. aureus, E. coli, and K. pneumonia.⁷⁶ Another conjugate of testosterone and vitamin B1 inhibited the growth of S. aureus, E. coli, and K. pneumonia.⁷⁷

The drug repurposing approach has been widely explored in order to identify potential candidates against fungal biofilms particularly formed on catheters and medical devices. Investigations on finasteride (Fig. 5C), a 5α-reductase inhibitor commonly used to treat benign prostatic hyperplasia, against C. albicans urinary biofilms either alone or in combination with amphotericin B or fluconazole, revealed high synergistic activity. Finasteride significantly impairs filament formation and disrupts cell membrane integrity, thus suggesting its potential mechanism of action.⁷⁸

Corticosteroids like prednisone inhibit immune cell responses in HIV-infected patients and also increase CD4 cell counts (cells of the immune system that fight infection). Hence, it is considered to be safe and effective for the therapeutic management of AIDS.⁷⁹ Further, a combination of high-dose dexamethasone and antiretroviral therapy successfully improved the platelet count and prevent severe thrombocytopenia or bleeding in HIV patients. Notably, dexamethasone is cost-effective as compared to other treatments such as immunoglobulin or rituximab.⁸⁰ In cholestatic hepatitis A patients, prednisolone administration improved the prognosis and also helped to get relief from accompanied pruritus (itching under the skin). Improving the actions of mpr2 protein, which increases the transport of bilirubin to hepatocytes, and its anti-inflammatory potential are the suggested mechanisms of action of prednisolone (Fig. 5C).⁸¹

3.4. Steroids for miscellaneous conditions

3.4.1. Cardiovascular diseases

Dexamethasone produces cardioprotective effects through different mechanisms. Repetitive subcutaneous administration of low doses of dexamethasone in combination with vitamin-D exerts atheroprotective effects through activation of the IL-10-producing network of lymphoid and myeloid immune cells.⁷⁹ Further, dexamethasone also improves cardiac functions in myocardial ischemia/reperfusion (MIR) by eliminating reactive oxygen species (ROS), inhibiting inflammatory and activating antioxidative responses.⁸² In Japan, a study (January 2005 and May 2014) conducted in-hospital and out-of-hospital patients suggested improved survival rates in patients with cardiac arrest after hydrocortisone administration.⁸³ It has been reported that dexamethasone exerts beneficial effects in the treatment of acute myocardial infarction through the rapid and non-transcriptional activation of endothelial nitric oxide synthase (eNOS), which promotes nitric oxide-dependent vasorelaxation, and also reduces myocardial infarct size following ischemia and reperfusion injury.⁸⁴

In another study, it was observed that the treatment with prednisone activates cGMP/PKG signalling and regulates cardiac remodelling and sodium water reabsorption in the kidneys and reduces blunted cGMP/PKG signalling responsible for impaired cardiac functioning and increased stiffness due to irregular heart muscle contractility and remodelling.⁸⁵

3.4.2. Epilepsy

Corticosteroids have been reported to be safe in epilepsy with clinical reduction of seizures as well as improvement in electroencephalogram (EEG).⁸⁶ The treatment using mainly prednisolone or methylprednisolone plus prednisone significantly lowers down the epileptic seizures. The steroidal drugs modulate both humoral and cellular immune processes and also display anti-inflammatory effects within the brain. Further, they also repair the blood–brain barrier and reduce entry of cytotoxic T-cells into the CNS. In another study conducted on 18 months to 10 years old children (both boys and girls), prednisone therapy remarkably reduced the seizure frequency.^86,87 Hence, prednisone is contemplated as an alternative medication in children with intractable generalized epilepsy non-responsive to conventional antiepileptic therapy.^86–88

3.4.3. Alopecia areata

Corticosteroids have also been repurposed to treat different types of alopecia especially alopecia areata, which is an autoimmune disorder leading to unpredictable hair loss. Topical steroids such as hydrocortisone, clobetasol propionate (Fig. 5D) usually remain the first line therapy followed by steroid injections (triamcinolone acetonide, Fig. 5D) and oral steroids (dexamethasone, prednisone, methylprednisolone). Steroidal drugs prevent the immune system from damaging hair follicles and then trigger hair regrowth in such patients.^89,90

4. Challenges with steroid therapeutics

Steroidal drugs are widely used as medications in numerous diseases such as cancer, inflammation, asthma, neurological disorders, and many more. Steroids are extremely effective drugs and can be administered by mouth, applied to the skin or eyes, inhaled, or injected into a muscle, joint, or vein. In spite of their significant potency and efficacy, the undesirable effects of steroidal drugs limit their therapeutic utility. The risks associated with steroids are related to the dose and duration of therapy. Generally, low systemic doses for short-term courses do not cause any significant adverse effects; however the chronic administration of corticosteroids may result in undesirable side effects and toxicities such as weight gain, high blood sugar, diabetes, weakening of the bones (osteoporosis), glaucoma, cataracts, acne, and mental problems. Although the use of anabolic steroids boosts muscle mass and athletic performance, such therapy comes with its own sets of challenges and could result in severe health problems like liver damage, cardiovascular diseases, mood swings and anxiety. Likewise, the use of sex steroids in certain hormone related diseases might lead to hormonal irregularities by disturbing the body's hormonal equilibrium prompting a score of adverse consequences.

Drug interactions of steroids with anti-coagulants, anti-diabetics, diuretics, and anti-hypertensives are also seen, which might alter their therapeutic potential either by making the medicine ineffective or having side effects more than usual. Moreover, discontinuation of the use of steroidal drugs may produce withdrawal symptoms like fatigue, weight loss, weakness, lower blood pressure, and menstrual changes.^91,92 Collectively, all these concerns are primary challenges with steroidal therapeutics.

Adverse effects and toxicities

Steroidal drugs can cause a wide array of undesirable side effects and also produce life-threatening and unavoidable toxicities. Irrespective of the severity and type of the underlying disease, type of steroidal agent, old age and route of administration are mainly responsible for undesirable effects, however, the treatment protocol remains the most significant and well-established risk factor.^93,94 The possibility of the adverse effects and toxicities appearing during or after the long term high-dose steroid therapy could be visualized in Table 5.

Table 5. Adverse effects and toxicities of long term high-dose steroid therapy^93,94.

Steroidal drugs	Adverse effects and toxicities
Oral corticosteroids	Weight gain, immune suppression, fatigue
	Muscle weakness, osteoporosis
	High blood pressure and blood sugar
	Delayed puberty and hirsutism
	Psychological effects
Inhaled corticosteroids	Hoarse or croaky voice,
	Sore mouth or throat, cough
Topical corticosteroids	Acne and warts
	Thin skin with lesions
	Inflamed hair follicles (folliculitis)
Injected corticosteroids	Facial flushing
	Insomnia
Anabolic steroids	Liver damage
	Cardiovascular diseases
	Mood swings and anxiety
Sex steroids	Hormonal irregularities
	Breast enlargement
	Reduced sperm count

Contraindications

Contraindications with steroidal drugs means hypersensitivity to the components of the formulation which may produce unwanted or dangerous reactions during the treatment in different patients. It could happen due to simultaneous administration of steroids with immunosuppressive medicines and also with steroid therapy in patients with clinical conditions like osteoporosis, uncontrolled hyperglycaemia, diabetes mellitus and glaucoma. Additionally, steroids should be used with utmost care in patients suffering from peptic ulcer, uncontrolled hypertension, congestive heart failure, renal failure, herpes simplex keratitis, and varicella infection.^93,95

Withdrawal syndrome

Steroid withdrawal syndrome (SWS) usually refers to relapse of the disease after withdrawal or rapidly reduced doses of corticosteroids. SWS commonly remains underdiagnosed and untreated as the mechanism of its occurrence remains obscure and could result in significant patient morbidity. Withdrawal may also produce a broad array of symptoms which include fever, nausea, anorexia, lethargy, malaise, arthralgias, desquamation of the skin, and weight loss with highly variable grading in patients with rapidly reduced to a low maintenance dose. Other less common symptoms include abdominal pain, vomiting, postural hypotension, hyponatremia, and hyperkalemia.^96,97

Steroids are the important regulators of diverse physiological activities and are often used in the treatment of a wide variety of diseases. However, the use of steroids also carries a burden of associated risks of side effects. Therefore, basic knowledge of the pharmacology, clinical usage guidelines, and contraindications of these agents is imperative for therapeutic usefulness. The general strategies to get the maximum therapeutic benefit of steroid therapy with the least number of risks are i) lower or intermittent doses for a short duration of time; ii) switching to non-oral forms such as inhaled corticosteroids for asthma to reach directly to the lung surfaces to minimize the side effects; iii) calcium and vitamin D supplements to help protect the bones; iv) careful withdrawal after long term steroid administration to avoid fatigue, body aches, sudden drop in blood pressure and low blood sugar levels; v) wearing a medical alert bracelet to monitor the dose and intervals properly; and vi) patient counselling to avoid and manage the adverse effects.^93,98,99 All these approaches along with proper patient education and counselling could prevent morbidity and reduce the life threating risks in patients on corticosteroid therapy.

5. Future perspectives for steroidal therapy

Steroidal drugs are available as the most effective therapeutic agents against numerous diseases but side effects limit their uses. This makes us want to develop novel, better and safer perspectives regarding the use of steroids in the near future. Development of novel drug delivery techniques to overcome the short biological half-life and poor solubility of drug molecules in biological fluids is a brand new area.^100–102 The features and medical applications of different delivery systems used in steroid therapy have been compiled in Table 6. Real time monitoring and supervision of the steroidal therapy would make them more advanced and more specific with the course of time.¹⁰⁰ Further, the technological innovations mainly artificial intelligence (AI) outweigh the risk factors accompanying the use of steroids by helping to diagnose diseases more accurately, assisting in medical decisions and providing an efficient treatment option.¹⁰¹ AI has the potential to revolutionize the steroid therapy and improve patient outcome by enabling more personalized and effective treatment plans, reducing the risk of adverse reactions, and facilitating the development of new and better regimes. However, it is important to remember that AI is still in the early stages of development and further research is required to fully evaluate its potential benefits and limitations through rigorous clinical trials and real-world experience.

Table 6. Features and medical applications of various delivery systems in steroid therapy^{100,102–111}.

Delivery system	Benefits	Examples
Liposomes: biocompatible vesicles composed of a phospholipid-bilayer having structural resemblance to cell membrane that form small spheroids which carry both hydrophilic and lipophilic drugs	Improve efficacy	Prednisolone for inflammation and arthritis
	Enhance target specificity	Dexamethasone phosphate, budesonide phosphate and methylprednisolone phosphate against cancer
	Reduce toxicity	Dexamethasone liposomes against rheumatoid arthritis, atherosclerosis and colitis
		Oestrogen receptor-mediated liposomal drug delivery for treating melanoma
Nanoparticles (NPs) – amorphous or crystalline solid forms with size ranging from 10 to 200 nm available as solid lipid nanoparticles (SLNs), nanoemulsions, nanostructured lipid carriers (NLC), and lipid nanocapsules	Enhance drug permeation and retention rate	Topical corticosteroids against psoriasis and atopic dermatitis
	Controlled release to avoid adverse effects	Betamethasone acetate, beclomethasone dipropionate, dexamethasone for inflammatory and autoimmune diseases such as rheumatoid arthritis and psoriasis
		Testosterone and estrogen for hypogonadism and weak muscle growth
Polymer-drug conjugates – macromolecular copolymers mainly N-(2-hydroxypropyl) methacrylamide (HPMA) of steroidal drugs	Promote physical stability and prolonged retention in the circulation	Polymer–dexamethasone conjugates in inflammatory diseases
Microspheres – naturally biodegradable free flowing powders made of proteins or synthetic polymers with a particle size less than 200 μm	Alternate to steroid multiple dosage regimens	Prednisolone in arthritis therapy
		Testosterone microspheres for the therapy of fecal incontinence

6. Conclusions

Steroidal drugs play a vital role in the field of medicine, providing significant therapeutic benefits against a wide variety of diseases by alleviating their symptoms and improving the quality of life of many patients. However, their responsible use requires a balance between the potential benefits and risks factors associated with these drugs. By carefully considering the indications, dosage, and monitoring, medical professionals can ensure the safe and effective use of steroidal drugs with minimum side-effects. Advances in scientific investigations by various research groups continue to provide detailed mechanistic insights and potential therapeutic applications of steroidal drugs. This results in deeper and improved understanding of their biological pathways to expand their potential uses beyond traditional applications. In the 21st century, as many as fifty three novel and repurposed steroidal drugs with diverse medicinal applications have been developed and approved by the US Food and Drug Administration (FDA). Their mechanisms of action against different diseases are recognised and well established. Out of the total yearly approved drugs by the FDA, the percentage of steroidal dugs remains quite good (∼6%). A big number of steroidal drug candidates are in various phases of clinical trials for cancer, inflammation, asthma, psoriasis, neurodegenerative disorders and cardiovascular diseases. Moreover, the development of targeted delivery systems and novel formulations of steroids has resulted in enhanced efficacy, minimum side effects, and improved patient outcomes. Repurposing of steroidal drugs in novel therapeutic areas due to their unique physiochemical properties has offered potential therapeutic benefits. Recently, their role in COVID-19 and neurodegenerative diseases has firmly contributed to the renewed interest in steroid research. These developments have sparked the enthusiasm and excitement among researchers and healthcare professionals toward these drugs. However, it is pertinent to keep in mind that with steroidal drugs caution must be exercised to ensure their appropriate and responsible use to maximize their potential benefits while minimizing the possible drawbacks.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of the review entitled ‘Revisiting the role of steroidal therapeutics in the 21st century: an update on FDA approved steroidal drugs (2000–2024)’.

Author contributions

Ranjit Singh: writing – original draft, methodology, investigation, visualization, Ranju Bansal: supervision, writing – review & editing. Both authors have read and agreed to the published version of the manuscript.

Conflicts of interest

The authors declare no conflict of interest.

Biographies

Biography

Ranjit Singh.

Dr Ranjit Singh works as Young Scientist at UIPS, Panjab University, Chandigarh, India. He got his doctoral degree in 2017 for his work on the synthesis of novel neuroprotective heterosteroids from the same department under the mentorship of Prof. Ranju Bansal. He has 23 publications in reputed scientific journals. He has been awarded the “PharmInnova Award 2019 – Best Thesis in Pharmaceutical Sciences” under the PhD section by Rajnibhai V Patel Trust, Gujrat (India). His research interests include the design, synthesis and pharmacological evaluation of heterosteroids for their medicinal applications against Alzheimer's and Parkinson's disease.

Biography

Ranju Bansal.

Dr Ranju Bansal is a Professor of Pharmaceutical Chemistry at UIPS, Panjab University, Chandigarh, India. She is an active researcher and academician for the last 28 years. She has around 110 research publications and several patents to her credit. She is a Commonwealth Academic Staff Fellow and UGC research awardee. Till date, 20 students have completed Ph. D. under her guidance. She has widely travelled in India and abroad and is also successfully collaborating with various national and international scientists. Her research interests include design and development of new chemical entities of medicinal significance.