METHODS FOR THE USE OF PROGESTOGEN AS A GLUCOCORTICOID SENSITIZER

• US 20110195031A1
• Filed: 02/07/2011
• Published: 08/11/2011
• Est. Priority Date: 02/08/2010
• Status: Active Grant

• Current Assignee: Shenzhen Evergreen Therapeutics Co., Ltd.
• Original Assignee: Prairie Pharmaceuticals, LLC
• Inventors: Du, Tao Tom
• Granted Patent: US 10,231,976 B2
• Time in Patent Office: Days
• US Class Current: 424/43
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/44 : Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Provided are methods and kits for administering progestogen as a glucocorticoid sensitizer to restore corticosteroid sensitivity or reverse the glucocorticoid insensitivity or enhance glucocorticoid sensitivity, in order to treat one or more glucocorticoid insensitivity related diseases or conditions. For example, these include methods for reversing the glucocorticoid insensitivity in a subject having no history of menstrual cycle-related exacerbation or allergy to self-hormones, particularly progesterone, such as premenstrual or perimenstrual deterioration in the symptoms, e.g., premenstrual worsening of atopic dermatitis or premenstrual exacerbations of asthma, and exhibiting relatively or totally refractory responses to glucocorticoid therapy, e.g., glucocorticoid resistance. The methods and kits provide for the administration of a sex hormone to the subject who is corticosteroid dependent or corticoid resistant or unresponsive or intolerant to corticosteroids.

Claims

1. A method for the treatment of glucocorticoid insensitivity, restoring corticosteroid sensitivity, enhancing glucocorticoid sensitivity or reversing the glucocorticoid insensitivity in a subject experiencing corticosteroid dependence or corticoid resistance or unresponsiveness or intolerance to corticosteroids, comprising administering a pharmaceutical composition comprising a steroid hormone (progestogen) as a glucocorticoid sensitizer to the subject exhibiting one or more glucocorticoid insensitivity related conditions, wherein the subject has no history of menstrual cycle-related exacerbation, and further wherein the glucocorticoid insensitivity related conditions comprise a range of immune-inflammatory disorders/diseases treated with steroids when the therapy fails to achieve disease control or is not effective or intolerant or dependent to corticosteroids, and combinations thereof.

5. The method of claim 1, further comprising evaluating whether the subject exhibits the one or more glucocorticoid insensitivity related diseases, disorders, or conditions.

6. The method of claim 1, wherein the steroid hormone is a progestogen.

7. The method of claim 1, wherein the pharmaceutical composition is designed to inhibit or delay the onset of the disease or disorder, reduce the risk of relapse, achieve a full or partial reduction of the symptoms or disease state, and alleviate, ameliorate, lessen, or cure the disease, disorder or symptoms.

8. The method of claim 1, wherein the subject is male or female at any age and exhibits the one or more glucocorticoid insensitivity related diseases, disorders, or conditions.

9. The method of claim 1, wherein the pharmaceutical composition is administered daily.

10. The method of claim 1, wherein the pharmaceutical composition is administered according to a dosing regimen selected from the group consisting of an administration interval less than one week, once weekly or exceeding once per week.

11. The method of claim 10, wherein the interval is selected from the group consisting of once per day, twice per day, three times per day, up to 24 times per day, and continuous infusion.

12. The method of claim 10, wherein the interval is selected from the group consisting of once every other week, once monthly, once every two months, and once every three months.

13. The method of claim 1, wherein the pharmaceutical composition is administered once monthly.

14. The method of any claim 1, wherein the pharmaceutical composition is administered systemically or locally delivered by a method selected from the group consisting of parenteral, intravenous, pulmonary, oral, rectal, buccal, transdermal, intravaginal delivery, local application, topical application, depot injection, subcutaneous, intraperitoneal, intraarterial and intramuscular injection.

15. The method of claim 14, wherein the transdermal delivery is administered by a formulation selected from the group consisting of a patch, cream, gel, and spray.

16. The method of claim 14, wherein the intravaginal delivery is administered by a formulation selected from the group consisting of a suppository, gel, and cream.

17. The method of claim 14, wherein the pulmonary drug delivery is administered by a formulation selected from the group consisting of a medical aerosol and an inhalant delivery device.

18. The method of any claim 1, wherein the progestogen is a progestin.

19. The method of any claim 1, wherein the progestogen is selected from the group consisting of progesterone, retroprogesterone, progesterone derivative, 17α

-OH progesterone derivatives (both pregnanes and norpregnanes), 19-norprogesterone derivatives, 19-nortestosterone derivatives (both estranges and gonanes), spironolactone derivatives, and a combination thereof.

20. The method of claim 1, wherein the progestogen is selected from the group consisting of 17alpha-hydroxyprogesterone or a derivative thereof, natural progesterone, dydrogesterone or a derivative or metabolite thereof, medrogestone or a derivative or metabolite thereof, medroxyprogesterone or a derivative or metabolite thereof, megestrol or a derivative or metabolite thereof, chlormadinone or a derivative or metabolite thereof, cyproterone or a derivative or metabolite thereof, gestonorone or a derivative or metabolite thereof, nomegestrol or a derivative or metabolite thereof, demegestone or a derivative or metabolite thereof, promegestone or a derivative or metabolite thereof, nestorone or a derivative or metabolite thereof, trimegestone or a derivative or metabolite thereof, norethisterone, norethisterone or a derivative or metabolite thereof, lynestrenol or a derivative or metabolite thereof, ethynodiol or a derivative or metabolite thereof, diacetate, norgestrel or a derivative or metabolite thereof, levonorgestrel or a derivative or metabolite thereof, desogestrel or a derivative or metabolite thereof, etonogestrel (3-keto-desogestrel) or a derivative or metabolite thereof, gestodene or a derivative or metabolite thereof, norgestimate or a derivative or metabolite thereof, norelgestrornin (17-deacetyl norgestimate) or a derivative or metabolite thereof, dienogest or a derivative or metabolite thereof, drospirenone or a derivative or metabolite thereof, norethindrone or a derivative or metabolite thereof, norethynodrel or a derivative or metabolite thereof, norgestrel or a derivative or metabolite thereof, drospirenone or a derivative thereof, or metabolite or a derivative thereof, etonogestrel or a derivative or metabolite thereof, 19-nortestosterone or a derivative or metabolites thereof, dienogest or a derivative or metabolite thereof, norethynodrel or a derivative or metabolite thereof, cyproterone or a derivative or metabolite thereof, tibolone or a derivative or metabolite thereof, 19-norprogesterone or a derivative or metabolite thereof, and combinations thereof.

21. The method of claim 20, wherein the derivative of progestogen is selected from the group consisting of an amine salt, alkali metal salt, transition metal salt, other metal salt, salt of a mineral acid, salt of an organic acid, an ester, enol ether or ester, acid, base, solvate, hydrate or prodrug prior to formulation.

22. The method of claim 21, wherein the derivative of 17alpha-hydroxyprogesterone is a carboxylic acid ester of 17alpha-hydroxyprogesterone.

23. The method of claim 21, wherein the derivative of medroxyprogesterone is medroxyprogesterone acetate, the derivative of megestrol is megestrol acetate, the derivative of chlormadinone is chlormadinone acetate, the derivative of cyproterone is cyproterone acetate, the derivative of gestonorone is gestonorone caproate, the derivative of nomegestrol is nomegestrol acetate, the derivative of norethisterone is norethisterone acetate, and the derivative of ethynodiol is ethynodiol diacetate.

24. The method of claim 1, wherein the progestogen is administered prior to, simultaneously with, or following the administration of glucocorticoid.

25. The method of claim 1, wherein the glucocorticoid is selected from the group consisting of hydrocortisone (cortisol), cortisone acetate, dexamethasone, prednisone, prednisolone, methylprednisolone, betamethasone, triamcinolone, beclometasone, Paramethasone, fluticasone, fludrocortisone acetate, deoxycorticosterone acetate (DOCA), Fluprednisolone, fluticasone propionate, budesonide, beclomethasone dipropionate, flunisolide and triamcinolone acetonide.

26. The method of claim 1, further comprising one or more additional treatments for restoring corticosteroid sensitivity or reversing the glucocorticoid insensitivity or enhancing glucocorticoid sensitivity to treat one or more glucocorticoid insensitivity related conditions.

27. The method of claim 26, wherein the one or more additional treatments are selected from the group consisting of an androgen, an estrogen, immunosuppressive or immunomodulator agent, calcineurin inhibitor, p38 MAP kinase inhibitor, JNK inhibitor, Vitamin D, MIF inhibitor, Histone deacetylate-2 activator, Theophylline, Phosphoinositide-3-kinase-δ

inhibitor, antioxidant, iNOS inhibitor, P-glycoprotein inhibitor, and combinations thereof.

28. The method of claim 26, wherein the progestogen is administered prior to, simultaneously with, or following the administration of an agent selected from the group consisting of dehydroepiandrosterone (DHEA), estradiol, cyclosporine, methotrexate, gold, 6-mercaptopurine, infliximab, etanercept, adalimumab, intravenous immunoglobulin, Mepolizumab, cyclosporin, tacrolimus, p38 MAP kinase inhibitor, JNK inhibitor, Vitamin D, MIF inhibitor, Histone deacetylate-2 activator, Theophylline, Phosphoinositide-3-kinase-δ

inhibitor, antioxidant, iNOS inhibitor, P-glycoprotein inhibitor, and combinations thereof.

29. The method of claim 1, wherein the pharmaceutical composition is administered to the subject via oral ingestion, further wherein the composition comprises from about 0.001 to 100 mg/kg of body weight of progestogen given orally per day.

2. A method for the treatment of glucocorticoid insensitivity related diseases, or disorders, or conditions, the method comprising:

administering a pharmaceutical composition comprising a steroid hormone (progestogen) as a glucocorticoid sensitizer to a subject exhibiting the glucocorticoid insensitivity, wherein the glucocorticoid insensitivity comprises corticosteroid dependence or corticoid resistance or unresponsiveness or intolerance to corticosteroids, and wherein the subject has no history of menstrual cycle-related exacerbation.

3. The method of claim 2, wherein the effects of the administration of the glucocorticoid sensitizer include, but are not limited to, steroid-sparing in corticosteroid-dependent patients, better responsiveness or tolerance to corticosteroids, achieving efficacy by using a lower dose of corticosteroid, preventing individuals at risk from developing refractory or resistance or exacerbations in response to antigen exposures, infections, exercise, or irritants, achieving optimal immune-functions, easier administrations of steroids that can be tapered or withdrawn, or reducing intolerance to prolonged administration of corticosteroids, decreased risks for developing corticosteroid-related adverse events such as opportunistic infections and bone loss, and combinations thereof.

4. A method for restoring corticosteroid sensitivity or reversing the glucocorticoid insensitivity or enhancing glucocorticoid sensitivity to treat one or more glucocorticoid insensitivity related conditions selected from the group consisting of a range of corticoid resistant diseases and immune-inflammatory disorders treated with glucocorticoid when the therapy becomes ineffective or intolerant or dependent or unresponsive or refractory to corticosteroids, and combinations thereof, the method comprising administering a pharmaceutical composition comprising a steroid hormone to a subject having no history of menstrual cycle-related exacerbation and wherein the subject exhibits one or more glucocorticoid insensitivity related diseases, disorders, or conditions selected from the group consisting of glucocorticoid resistant asthma, refractory rheumatoid arthritis, refractory inflammatory bowel disease, chronic obstructive pulmonary disease, acute respiratory distress syndrome, interstitial pulmonary fibrosis, cystic fibrosis, refractory ulcerative colitis, children with severe Crohn disease, corticosteroid refractory asthma, desquamative interstitial pneumonia refractory to corticosteroid, refractory inflammatory myopathies, refractory myasthenia gravis, refractory pemphigus vulgaris, methotrexate-refractory RA patients, refractory nephrotic syndrome, refractory multiple sclerosis, refractory sprue-like disease, steroid-resistant sarcoidosis, refractory mucosal lesions of pemphigus vulgaris, refractory Schnitzler syndrome, resistant dermatitis of the head and neck, severe refractory atopic dermatitis, refractory Idiopathic thrombocytopenia purpura, refractory orbital myositis, refractory or recurrent lymphomas, critically ill patients with sepsis or acute respiratory distress syndrome (ARDS) and relative adrenal insufficiency, rosacea, polymyalgia rheumatic, giant cell arteritis, polymyositis, dermatomyositis, Kawasaki syndrome, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, Stiff man syndrome, corticosteroid dependent systemic lupus erythematosus, corticosteroid dependent multiple sclerosis, symptomatic corticosteroid dependent asthma, primary Sjogren'"'"'s syndrome, systemic vasculitis, polymyositis, organ transplants, graft-versus-host disease, inflammatory diseases, autoimmune diseases, hyperproliferative diseases, lupus, osteoarthritis, rhinosinusitis, polyarteritis nodosa, Wegener'"'"'s granulomatosis, giant cell arteritis, allergic rhinitis, urticaria, hereditary angioedema, tendonitis, bursitis, autoimmune chronic active hepatitis, cirrhosis, transplant rejection, psoriasis, dermatitus, malignancies, leukemia, myelomas, lymphomas, acute adrenal insufficiency, rheumatic fever, granulomatous disease, immune proliferation/apotosis, hypothalamic-pituitary-adrenal (HPA) axis suppression and regulation, hypercortisolemia, modulation of the Th1/Th2 cytokine balance, chronic kidney disease, spinal cord injury, cerebral edema, thrombocytopenia, Little'"'"'s syndrome, Addison'"'"'s disease, autoimmune hemolytic anemia, uveitis, pemphigus vulgaris, nasal polyps, sepsis, bacterial infections, viral infections, rickettsial infections, parasitic infections, type II diabetes, obesity, metabolic syndrome, depression, schizophrenia, mood disorders, Cushing'"'"'s syndrome, anxiety, sleep disorders, memory and learning enhancement, glucocorticoid-induced glaucoma, atopic dermatitis, drug hypersensitivity reactions, serum sickness, bullous dermatitis herpetiformis, contact dermatitis, exfoliative erythroderma, mycosis fungoides, pemphigus, nonsuppurative thyroiditis, sympathetic ophthalmia, uveitis, ocular inflammatory conditions unresponsive to topical steroids, allergic bronchopulmonary aspergillosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate chemotherapy, hypersensitivity pneumonitis, idiopathic bronchiolitis obliterans with organizing pneumonia, idiopathic eosinophilic pneumonias, idiopathic pulmonary fibrosis, pneumocystis carinii pneumonia (PCP) associated with hypoxemia occurring in an HIV(+) individual who is also under treatment with appropriate anti-PCP antibiotics, a diuresis or remission of proteinuria in nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatic, psoriatic arthritis, relapsing polychondritis, trichinosis with neurologic or myocardial involvement, and tuberculous meningitis.

30. A kit comprising a pharmaceutical composition, wherein the pharmaceutical composition comprises a steroid hormone, one or more pharmaceutically acceptable excipients, and instructions for administering the pharmaceutical composition to a subject having no history of menstrual cycle-related exacerbation, wherein the subject exhibits one or more glucocorticoid insensitivity related conditions.

34. The kit of claim 30, further comprising instructions for evaluating whether the subject exhibits the one or more glucocorticoid insensitivity related diseases, disorders, or conditions.

36. The kit of claim 30, wherein the steroid hormone is a progestogen.

37. The kit of claim 30, wherein the pharmaceutical composition is designed to inhibit or delay the onset of the disease or disorder, reduce the risk of relapse, achieve a full or partial reduction of the symptoms or disease state, or alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms.

38. The kit of claim 30, wherein the subject is male or female of any age, and exhibits the one or more glucocorticoid insensitivity related diseases, disorders, or conditions.

39. The kit of claim 30, wherein the instructions comprise instructions for administering the pharmaceutical composition daily.

40. The kit of any claim 30, wherein the instructions comprise instructions for administering the pharmaceutical composition at an interval less than one week, once weekly or exceeding once per week.

41. The kit of claim 30, wherein the instructions comprise instructions for administering the pharmaceutical composition at an interval selected from the group consisting of once per day, twice per day, three times per day, up to 24 times per day, and by continuous infusion.

42. The kit of claim 30, wherein the instructions comprise instructions for administering the pharmaceutical composition at an interval selected from the group consisting of once every other week, once monthly, once every two months, and once every three months.

43. The kit of claim 30, wherein the instructions comprise instructions for administering the pharmaceutical composition once monthly.

44. The kit of claim 30, wherein the instructions comprise instructions for administering the pharmaceutical composition by a method selected from the group consisting of parenteral, intravenous, pulmonary, oral, rectal, buccal, transdermal, intravaginal delivery, local application, topical application, depot injection, subcutaneous, intraperitoneal, intraarterial, and intramuscular injection.

45. The kit of claim 44, wherein the instructions comprise instructions for administering the pharmaceutical composition transdermally via a formulation selected from the group consisting of a patch, cream, gel, and spray.

46. The kit of claim 44, wherein the instructions comprise instructions for administering the pharmaceutical composition intravaginally via a formulation selected from the group consisting of a suppository, gel, and cream.

47. The kit of claim 44, wherein the instructions comprise instructions for administering the pharmaceutical composition pulmonarily via a formulation selected from the group consisting of an inhaled medical aerosol and an inhalant delivery device.

48. The kit of claim 30, wherein the progestogen is a progestin.

49. The kit of claim 30, wherein the progestogen is selected from the group consisting of progesterone, retroprogesterone, progesterone derivative, 17a-OH progesterone derivatives (both pregnanes and norpregnanes), 19-norprogesterone derivatives, 19-nortestosterone derivatives (both estranges and gonanes), spironolactone derivatives, and a combination thereof.

50. The kit of claim 30, wherein the progestogen is selected from the group consisting of 17alpha-hydroxyprogesterone or a derivative thereof, natural progesterone, dydrogesterone or a derivative or metabolite thereof, medrogestone or a derivative or metabolite thereof, medroxyprogesterone or a derivative or metabolite thereof, megestrol or a derivative or metabolite thereof, chlormadinone or a derivative or metabolite thereof, cyproterone or a derivative or metabolite thereof, gestonorone or a derivative or metabolite thereof, nomegestrol or a derivative or metabolite thereof, demegestone or a derivative or metabolite thereof, promegestone or a derivative or metabolite thereof, nestorone or a derivative or metabolite thereof, trimegestone or a derivative or metabolite thereof, norethisterone or a derivative or metabolite thereof, lynestrenol or a derivative or metabolite thereof, ethynodiol or a derivative or metabolite thereof, norgestrel or a derivative or metabolite thereof, levonorgestrel or a derivative or metabolite thereof, desogestrel or a derivative or metabolite thereof, etonogestrel (3-keto-desogestrel) or a derivative or metabolite thereof, gestodene or a derivative or metabolite thereof, norgestimate or a derivative or metabolite thereof, norelgestromin (17-deacetyl norgestimate) or a derivative or metabolite thereof, dienogest or a derivative or metabolite thereof, drospirenone or a derivative or metabolite thereof, norethindrone or a derivative or metabolite thereof, norethynodrel or a derivative or metabolite thereof, norgestrel or a derivative or metabolite thereof, drospirenone or a derivative or metabolite thereof, etonogestrel or a derivative or metabolite thereof, 19-nortestosterone or a derivative or metabolite thereof, dienogest or a derivative or metabolite thereof, norethynodrel or a derivative or metabolite thereof, cyproterone or a derivative or metabolite thereof, tibolone or a derivative or metabolite thereof, 19-norprogesterone or a derivative or metabolite thereof, and combinations thereof.

51. The kit of claim 30, wherein the progestogen is selected from the group consisting of the corresponding progestogen amine salt, alkali metal salt, transition metal salt, other metal salt, salt of a mineral acid, salt of an organic acid, ester, enol ether or ester, acid, base, solvate, hydrate, and prodrug prior to formulation.

52. The kit of claim 51, wherein the derivative of 17alpha-hydroxyprogesterone is a carboxylic acid ester of 17alpha-hydroxyprogesterone.

53. The kit of claim 51, wherein the derivative of medroxyprogesterone is medroxyprogesterone acetate, the derivative of megestrol is megestrol acetate, the derivative of chlormadinone is chlormadinone acetate, the derivative of cyproterone is cyproterone acetate, the derivative of gestonorone is gestonorone caproate, the derivative of nomegestrol is nomegestrol acetate, the derivative of norethisterone is norethisterone acetate, and the derivative of ethynodiol is ethynodiol diacetate.

54. The kit of claim 30, wherein the instructions comprise instructions for administering the progestogen prior to, simultaneously with, or following the administration of glucocorticoid.

55. The kit of claim 54, wherein the derivative of glucocorticoid is selected from the group consisting of hydrocortisone (cortisol), cortisone acetate, dexamethasone, prednisone, prednisolone, methylprednisolone, betamethasone, triamcinolone, beclometasone, paramethasone, fluticasone, fludrocortisone acetate, deoxycorticosterone acetate (DOCA), Fluprednisolone, fluticasone propionate, budesonide, beclomethasone dipropionate, flunisolide and triamcinolone acetonide.

56. The kit of claim 30, wherein the instructions comprise instructions for providing one or more additional treatments for restoring corticosteroid sensitivity or reversing the glucocorticoid insensitivity or enhancing glucocorticoid sensitivity to treat one or more glucocorticoid insensitivity related conditions.

57. The kit of claim 56, wherein the one or more additional treatments are selected from the group consisting of an androgen, an estrogen, immunosuppressive or immunomodulator agent, calcineurin inhibitor, p38 MAP kinase inhibitor, JNK inhibitor, Vitamin D, MIF inhibitor, histone deacetylate-2 activator, theophylline, phosphoinositide-3-kinase-δ

inhibitor, antioxidant, iNOS inhibitor, p-glycoprotein inhibitor, and combinations thereof.

58. The kit of claim 30, wherein the instructions comprise instructions for administering the progestogen prior to, simultaneously with, or following the administration of an agent selected from the group consisting of dehydroepiandrosterone (DHEA), estradiol, cyclosporine, methotrexate, gold, 6-mercaptopurine, infliximab, etanercept, adalimumab, intravenous immunoglobulin, Mepolizumab, ciclosporin, tacrolimus, p38 MAP kinase inhibitor, JNK inhibitor, Vitamin D, MIF inhibitor, Histone deacetylate-2 activator, Theophylline, Phosphoinositide-3-kinase-δ

inhibitor, antioxidant, iNOS inhibitor, P-glycoprotein inhibitor, and combinations thereof.

59. The kit of claim 30, comprising a pharmaceutical composition comprising a steroid hormone and one or more pharmaceutically acceptable excipients;

and instructions for administering the pharmaceutical composition to the subject via oral ingestion, wherein the composition comprises from about 0.001 to 100 mg/kg of body weight of progestogen given orally per day, and further wherein the amount used with non-oral routes is determined based upon corresponding serum concentration level of an oral dosage or containing a quantity of the active compound in an amount sufficient to alleviate the symptoms of the treated subject.

31. A kit comprising a pharmaceutical composition, wherein the pharmaceutical composition comprises a steroid hormone, one or more pharmaceutically acceptable excipients, and instructions for administering the pharmaceutical composition as a glucocorticoid sensitizer to a subject exhibiting glucocorticoid insensitivity, wherein the subject has no history of menstrual cycle-related exacerbation.

32. A kit comprising a pharmaceutical composition, wherein the pharmaceutical composition comprises a steroid hormone, one or more pharmaceutically acceptable excipients, and instructions for administering the pharmaceutical composition as a glucocorticoid sensitizer to achieve the effects of steroid-sparing in corticosteroid-dependent patients, better responsiveness or tolerance to corticosteroids, achieving efficacy by using a lower dose of corticosteroid, preventing individuals at risk for developing refractory or resistance or exacerbations in response to antigen exposures, infections, exercise, or irritants, achieving optimal immune-functions, easier steroid tapered or withdrawn, or prolonged administration of corticosteroids, decreased risks for developing corticosteroid-related adverse events such as opportunistic infections and bone loss, and combinations thereof.

33. A kit comprising a pharmaceutical composition, wherein the pharmaceutical composition comprises a steroid hormone and one or more pharmaceutically acceptable excipients;

and instructions for administering the pharmaceutical composition to a subject to treat one or more glucocorticoid insensitivity related conditions selected from the group consisting of corticoid resistant diseases and immune-inflammatory disorders treated with glucocorticoid when the therapy becomes ineffective or intolerant or dependent or unresponsive or refractory to corticosteroids, and combinations thereof, wherein the subject has no history of menstrual cycle-related exacerbation and exhibits one or more glucocorticoid insensitivity related diseases, disorders, or conditions selected from the group consisting of glucocorticoid resistant asthma, refractory rheumatoid arthritis, refractory inflammatory bowel disease, chronic obstructive pulmonary disease, acute respiratory distress syndrome, interstitial pulmonary fibrosis, cystic fibrosis, refractory ulcerative colitis, severe Crohn'"'"'s disease, corticosteroid refractory asthma, desquamative interstitial pneumonia refractory to corticosteroid, refractory inflammatory myopathies, refractory myasthenia gravis, refractory pemphigus vulgaris, methotrexate-refractory RA patients, refractory nephrotic syndrome, refractory multiple sclerosis, refractory sprue-like disease, steroid-resistant sarcoidosis, refractory mucosal lesions of pemphigus vulgaris, refractory Schnitzler syndrome, resistant dermatitis of the head and neck, severe refractory atopic dermatitis, refractory Idiopathic thrombocytopenia purpura, refractory orbital myositis, refractory or recurrent lymphomas, sepsis, acute respiratory distress syndrome (ARDS), relative adrenal insufficiency, rosacea, polymyalgia rheumatic, giant cell arteritis, polymyositis, dermatomyositis, Kawasaki syndrome, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, Stiff man syndrome, corticosteroid dependent systemic lupus erythematosus, corticosteroid dependent multiple sclerosis, symptomatic corticosteroid dependent asthma, primary Sjogren'"'"'s syndrome, systemic vasculitis, polymyositis, organ transplants, graft-versus-host disease, inflammatory diseases, autoimmune diseases, hyperproliferative diseases, lupus, osteoarthritis, rhinosinusitis, polyarteritis nodosa, Wegener'"'"'s granulomatosis, giant cell arteritis, allergic rhinitis, urticaria, hereditary angioedema, tendonitis, bursitis, autoimmune chronic active hepatitis, cirrhosis, transplant rejection, psoriasis, dermatitus, malignancies, leukemia, myelomas, lymphomas, acute adrenal insufficiency, rheumatic fever, granulomatous disease, immune proliferation/apotosis, hypothalamic-pituitary-adrenal (HPA) axis suppression and regulation, hypercortisolemia, modulation of the Th1/Th2 cytokine balance, chronic kidney disease, spinal cord injury, cerebral edema, thrombocytopenia, Little'"'"'s syndrome, Addison'"'"'s disease, autoimmune hemolytic anemia, uveitis, pemphigus vulgaris, nasal polyps, sepsis, bacterial infections, viral infections, rickettsial infections, parasitic infections, type II diabetes, obesity, metabolic syndrome, depression, schizophrenia, mood disorders, Cushing'"'"'s syndrome, anxiety, sleep disorders, memory and learning enhancement, glucocorticoid-induced glaucoma, atopic dermatitis, drug hypersensitivity reactions, serum sickness, bullous dermatitis herpetiformis, contact dermatitis, exfoliative erythroderma, mycosis fungoides, pemphigus, bullous pemphigoid, nonsuppurative thyroiditis, sympathetic ophthalmia, uveitis, ocular inflammatory conditions unresponsive to topical steroids, allergic bronchopulmonary aspergillosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate chemotherapy, hypersensitivity pneumonitis, idiopathic bronchiolitis obliterans with organizing pneumonia, idiopathic eosinophilic pneumonias, idiopathic pulmonary fibrosis, pneumocystis carinii pneumonia (PCP) associated with hypoxemia occurring in an HIV(+) individual who is also under treatment with appropriate anti-PCP antibiotics, a diuresis or remission of proteinuria in nephritic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatic, psoriatic arthritis, relapsing polychondritis, trichinosis with neurologic or myocardial involvement, and tuberculous meningitis.

35. A kit comprising a pharmaceutical composition comprising a steroid hormone and one or more pharmaceutically acceptable excipients;

and instructions for administering the pharmaceutical composition.

60. A method of treating a smoking-induced glucocorticoid resistance disease, comprising administering at least one progestogen.

61. The method of claim 60, wherein the progestogen is selected from the group consisting of 17HPC, P4 and MPA.

62. The method of claim 60, wherein the disease is chronic obstructive pulmonary disease (COPD).