5α-reductase inhibitors (5-ARIs) are a class of drugs with antiandrogen effects, used primarily in the treatment of benign prostatic hyperplasia (BPH) and androgenic alopecia.
These agents inhibit the enzyme 5α-reductase, which is involved in the metabolic transformations of a variety of endogenous steroids. 5α-reductase inhibition is most known for preventing conversion of testosterone, the major androgen sex hormone, to the more potent dihydrotestosterone (DHT), in androgen-associated disorders.
Contents
- 1 Medical use
- 2 Adverse reactions
- 3 Pharmacology
- 3.1 Pharmaceuticals
- 3.2 Research
- 3.3 Basic structure of Azasteroids
- 4 Herbs and other inhibitors
- 5 References
Medical use
Propecia (finasteride) 1 mg tablets
Avodart (dutasteride) 500 µg capsules
5-ARIs are clinically used in the treatment of conditions that are exacerbated by DHT:[1]
- Mild-to-moderate benign prostatic hyperplasia and lower urinary tract symptoms
- Androgenic alopecia in both men and women
They have also been explored in the treatment and prevention of prostate cancer. However, their use for this indication is controversial, as some authors have expressed concern that they may inadvertently lead to development of more aggressive tumor variants.
5-ARIs are also sometimes employed as supplementary antiandrogens in hormone replacement therapy for trans women.
Adverse reactions
In general, adverse drug reactions (ADRs) experienced with 5-ARIs are dose-dependent. Common ADRs include impotence, decreased libido, decreased ejaculate volume, depression, and anxiety. Rare ADRs include breast tenderness and enlargement (gynecomastia), and allergic reaction.[1][2]
The FDA has notified healthcare professionals that the Warnings and Precautions section of the labels for the 5-ARI class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer).[3]
Finasteride is associated with intraoperative floppy iris syndrome and cataract formation.[4][5]
Pharmacology
The pharmacology of 5α-reductase inhibition is complex, but involves the binding of NADPH to the enzyme followed by the substrate. Specific substrates include testosterone, progesterone, androstenedione, epitestosterone, cortisol, aldosterone, and deoxycorticosterone. The entire physiologic effect of their reduction is unknown, but likely related to their excretion or is itself physiologic.[6] Beyond being a catalyst in the rate-limiting step in testosterone reduction, 5α-reductase isoforms I and II reduce progesterone to 5α-dihydroprogesterone (5α-DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC). In vitro and animal models suggest subsequent 3α-reduction of DHT, 5α-DHP and DHDOC lead to neurosteroid metabolites with effect on cerebral function. These neurosteroids, which include allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 5α-androstanediol, act as potent positive allosteric modulators of GABAA receptors, and have anticonvulsant, antidepressant, anxiolytic, prosexual, and anticonvulsant effects.[7] 5α-dihydrocortisol is present in the aqueous humor of the eye, is synthesized in the lens, and might help make the aqueous humor itself.[8] 5α-dihydroaldosterone is a potent antinatriuretic agent, although different from aldosterone. Its formation in the kidney is enhanced by restriction of dietary salt, suggesting it may help retain sodium as follows:[9]
-
-
- Substrate + NADPH + H+ → 5α-substrate + NADP+
5α-DHP is a major hormone in circulation of normal cycling and pregnant women.[10]
Inhibition of the enzyme can be classified into two categories: steroidal and nonsteroidal. The steroidal class has more inhibitors with examples including finasteride (MK-906), dutasteride (GG745), 4-MA, turosteride, MK-386, MK-434, and MK-963. Several have pursued synthesis of nonsteroidals to inhibit 5α-reductase due to the undesired side effects of steroidals. The most potent and selective inhibitors of 5α-R1 are found in this class, and include benzoquinolones, nonsteroidal aryl acids, butanoid acid derivatives, and more recognizably, polyunsaturated fatty acids (especially gamma-linolenic acid), zinc, and green tea.[6]
Inhibition of 5α-reductase results in decreased conversion of testosterone to DHT by reducing the Δ4,5 double-bond. This, in turn, results in slight elevations in testosterone and estradiol levels. Gynecomastia, sexual dysfunction, and depression, are some possible side effects of 5α-reductase inhibition.
Other enzymes compensate to a degree for the absent conversion, specifically with local expression at the skin of reductive 17β-hydroxysteroid dehydrogenase, and oxidative 3α-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase enzymes.[11]
In BPH, DHT acts as a potent cellular androgen and promotes prostate growth; therefore, it inhibits and alleviates symptoms of BPH. In alopecia, male and female-pattern baldness is an effect of androgenic receptor activation, so reducing levels of DHT also reduces hair loss.
Pharmaceuticals
Finasteride (Proscar or Propecia) inhibits the function of two of the isoenzymes (type II and III), whereas dutasteride inhibits all three.[12] Finasteride potently inhibits 5α-R2 at a mean inhibitory concentration IC50 of 69 nM, but is less effective with 5α-R1 until an IC50 of 360 nM.[13] Finasteride decreases mean serum level of DHT by 71% after 6 months,[14] and was shown in vitro to inhibit 5α-R3 at a similar potency to 5α-R2 in transfected cell lines.[15] Long term side effects can occur after discontinuation of the drug.[16]
Dutasteride (Avodart) has more complete suppression of all three 5α-reductase isoenzymes. It inhibits types 1 and 2 better than finasteride, leading to it causing further reduction in DHT at 6 months than the older drug (94.7% versus 70.8%).[17] It also reduces intraprostatic DHT 97% in men with prostate cancer at 5 milligrams per day over three months.[18] A second study with 3.5 mg/d for 4 months decreased intraprostatic DHT even further by 99%.[19] It has also been shown to inhibit the 5α-R3 isoenzyme in vitro,[20] suggesting that dutasteride may be a triple 5α reductase inhibitor in vivo.[6]
Alfatradiol (Ell-Cranell Alpha, Pantostin) is a topical 5-ARI used for androgenic alopecia in men and women.[21] [22]
Research
Some of the 5-ARIs in research are as follows:
| PNU 157706[23] |
4-MA |
LY 266111 |
L-751788 |
EM-402 |
|
|
|
|
|
|
| AS 97004 |
MK-386 |
Steroidal Oxime[24] |
MK-963 |
MK-434 |
|
|
|
|
|
|
| FR 146687[25] |
FK 143 |
Z-350 |
ONO-3805 |
|
|
|
|
|
|
|
- Bexlosteride (LY-191,704)
- Izonsteride (LY-320,236)
- LY-266111
- Epristeride (SKF-105,657, ONO-9302)
- (ONO-3805)
- Lapisteride (CS-891)
- Turosteride (FCE-26,073)
- FCE 28260
- AS 97004
- EM-402
- Z-350[26]
- L-751788 16-((4-chlorophenyl)oxy)-4,7-dimethyl-4-azaandronstan-3-one
- 4-MA (Dual inhibitor of both I & II isozymes (IC50 = 8.5 nM), but also 3-β-HSD inhibitor, investigated extensively but said to be hepatotoxic).[27]
- PNU-175706
- MK-386 (L-733692),
- MK-434 (17 beta-benzoyl-4-aza-5 alpha-androst-1-ene-3-one).[28]
- MK-963 (L-654066),[29]
- FR146687 and FK143 (Fujisawa Pharmaceutical) {Indolizine- and Indol-Butanoic Acids}
- 17β-carboxy-4-androsten-3-one {[30] in [31]}
- Steroidal Oxime.[32]
- Please read attached online resource for even more information on the subject.[33]
- For example, making the caproate ester of DHEA (#121) seems to work well as an inhibitor of 5-αR (IC50 = 0.049nM).[34]
Basic structure of Azasteroids
Basic structure of Azasteroids.
- Note: the possibility for cyclopropane ring juncture between carbon 1 and 2 on ring A also exist in structure B.
- Can also functionalize carbon 4 in this structure either with methyl or halogen, etc.
Some of the 6-azasteroids may prove to be useful drugs, but have yet to reach the pharmaceutical market.[35][36]
Herbs and other inhibitors
Many plants, as well as their associated phytochemical constituents, have inhibitory effects on 5α-reductase.[37] In addition, many of these compounds are also phytoestrogens.[38]
- Zinc.[39]
- Riboflavin (vitamin B2).[40]
- Azelaic acid,[39] (sometimes combined with minoxidil hair solution).
- β-sitosterol,[41] is just one of the many phytosterols.
- Polyphenols[42]
- Alizarin,[citation needed]
- Curcumin,[citation needed] the principal curcuminoid of turmeric.
- Green tea catechins, including (-)-epicatechin-3-gallate, and (-)-epigallo-catechin-3-gallate (EGCG).[43]
- Valoneic acid dilactone and gallagyldilactone are two hydrolysable tannin polyphenols isolated from the heartwood of Shorea laeviforia[44] and oaks species such as the North American white oak (Quercus alba) and European red oak (Quercus robur) are inhibitory.[45]
- Angelica koreana [46][47]
- Garden Balsam or Rose Balsam (Impatiens balsamina)[48]
- Pollen of Turnip, turnip rape, fast plants, field mustard, or turnip mustard (Brassica rapa)[49]
- Dodder (Cuscuta reflexa)[50]
- Euphorbia jolkinii[51][52]
- Lingzhi mushroom or Reishi mushroom (Ganoderma lucidum)[53][54][55][56]
- Ganoderic acid,[57] or Ganoderol B are thought to be the compounds in the mushroom that are specifically active.[58]
- Chinese Knotweed (Polygonum multiflorum),[59] contains resveratrol-like Stilbenoids.
- Black Pepper leaf extract (Piper nigrum) [60]
- Red Stinkwood (Pygeum africanum)[61]
- Saw Palmetto (Serenoa repens, active substance possibly lauric acid[62])[63][64]
- The berries of saw palmetto (Serenoa repens), a small palm native to the south east United States, possess a dual 5a-reductase inhibition activity, due to their high content of phytosterols: β-sitosterol, stigmasterol, lupeol, lupenone, and cycloartenol. Permixon® was launched in Europe in 1984 but has no FDA approval. The lipido-sterol extract markedly inhibits both the human isoenzymes. Type 1 isoenzyme is noncompetitively (Ki = 7.2 μg/mL) and type 2 isoenzyme uncompetitively (Ki = 4.9 μg/mL) inhibited[65]
- Pine (Pinus sp. resin, active substance abietic acid)[66]
- Ku Shen or Bitter root (Sophora flavescens)[67]
- Japanese hedge parsley (Torilis japonica)[68]
- Eastern Arborvitae, Northern Whitecedar (Thuja occidentalis)[69]
- Spore of Japanese climbing fern (Lygodium japonicum)[70]
- Further dual phytotherapeutic 5a-reductase inhibitors include, among other extracts of Pygeum africanum, Artocarpus altilis (breadfruit), Thuja orientalis, Laminaria saccharina, Arnica montana, Cinchona succirubra, Eugenia caryophyllata (cloves), Humulus lupulus (hops), Hypericum perforatum (St Johns wort), Mentha piperita (peppermint), Rosmarinus officinalis, Salvia officinalis (sage) and Thymus officinalis; furthermore, diterpens, flavins, and isoflavonoids such as genistein and daidzein, lignans, resveratrol, curcumin, and certain polyunsaturated fatty acids.
- The relative inhibitory potencies of unsaturated fatty acids are, in decreasing order: Gamma-Linolenic acid, alpha-linolenic acid, linoleic acid, palmitoleic acid, oleic acid, and myristoleic acid.[71]
- Medium chain fatty acids such as those found in coconut and the kernel of many palm fruits have also been found to inhibit 5α-reductase.[72]
- Certain pesticides are able to disturb the sex steroid hormone system and to act as antiandrogens.[73]
These supplements have limited testing in human clinical trials, and their potential for the treatment of BPH, androgenic alopecia, and related conditions is unknown.
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- ^ Hirata, N; Tokunaga, M; Naruto, S; Iinuma, M; Matsuda, H (2007). "Testosterone 5alpha-reductase inhibitory active constituents of Piper nigrum leaf.". Biological & Pharmaceutical Bulletin 30 (12): 2402–5. doi:10.1248/bpb.30.2402. PMID 18057734.
- ^ Edgar AD. Levin R. Constantinou CE. Denis L. "A critical review of the pharmacology of the plant extract of Pygeum africanum in the treatment of LUTS.Neurourology & Urodynamics. 26(4):458-63; discussion 464, 2007" [Review]
- ^ Raynaud, JP; Cousse, H; Martin, PM (2002). "Inhibition of type 1 and type 2 5alpha-reductase activity by free fatty acids, active ingredients of Permixon". The Journal of Steroid Biochemistry and Molecular Biology 82 (2–3): 233–9. doi:10.1016/S0960-0760(02)00187-5. PMID 12477490.
- ^ Pais, P (2010). "Potency of a novel saw palmetto ethanol extract, SPET-085, for inhibition of 5alpha-reductase II.". Advances in therapy 27 (8): 555–63. doi:10.1007/s12325-010-0041-6. PMID 20623347.
- ^ Abe, M; Ito, Y; Oyunzul, L; Oki-Fujino, T; Yamada, S (2009). "Pharmacologically relevant receptor binding characteristics and 5alpha-reductase inhibitory activity of free Fatty acids contained in saw palmetto extract.". Biological & Pharmaceutical Bulletin 32 (4): 646–50. doi:10.1248/bpb.32.646. PMID 19336899.
- ^ Iehlé, C.; Délos, S.; Guirou, O.; Tate, R.; Raynaud, J. P.; Martin, P. M. (1995). "Human prostatic steroid 5α-reductase isoforms—A comparative study of selective inhibitors". The Journal of Steroid Biochemistry and Molecular Biology 54 (5–6): 273–9. doi:10.1016/0960-0760(95)00134-L. PMID 7577710. edit
- ^ Roh, SS; Park, MK; Kim, YU (2010). "Abietic acid from Resina Pini of Pinus species as a testosterone 5α-reductase inhibitor". Journal of Health Science 56 (4): 451–455. doi:10.1248/jhs.56.451.
- ^ Roh, SS; Kim, CD; Lee, MH; Hwang, SL; Rang, MJ; Yoon, YK (2002). "The hair growth promoting effect of Sophora flavescens extract and its molecular regulation.". Journal of dermatological science 30 (1): 43–9. doi:10.1016/s0923-1811(02)00060-9. PMID 12354419.
- ^ Park, WS; Son, ED; Nam, GW; Kim, SH; Noh, MS; Lee, BG; Jang, IS; Kim, SE; Lee, JJ; Lee, CH (2003). "Torilin from Torilis japonica, as a new inhibitor of testosterone 5 alpha-reductase.". Planta medica 69 (5): 459–61. doi:10.1055/s-2003-39717. PMID 12802730.
- ^ Park, WS; Lee, CH; Lee, BG; Chang, IS (2003). "The extract of Thujae occidentalis semen inhibited 5alpha-reductase and androchronogenetic alopecia of B6CBAF1/j hybrid mouse.". Journal of dermatological science 31 (2): 91–8. doi:10.1016/s0923-1811(02)00146-9. PMID 12670719.
- ^ Matsuda H., Yamazaki M., Naruto S., Asanuma Y., Kubo M. "Anti-androgenic and hair growth promoting activities of Lygodii Spora (spore of Lygodium japonicum) I. Active constituents inhibiting testosterone 5α-reductase " Biological and Pharmaceutical Bulletin 2002 25:5 (622-626)
- ^ Liang, T.; Liao, S. (1992). "Inhibition of steroid 5 alpha-reductase by specific aliphatic unsaturated fatty acids". The Biochemical journal. 285 ( Pt 2) (Pt 2): 557–562. PMC 1132824. PMID 1637346. edit
- ^ Liu, J; Shimizu, K; Kondo, R (2009). "Anti-androgenic activity of fatty acids.". Chemistry & Biodiversity 6 (4): 503–12. doi:10.1002/cbdv.200800125. PMID 19353546.
- ^ Lo, S; King, I; Alléra, A; Klingmüller, D (2007). "Effects of various pesticides on human 5alpha-reductase activity in prostate and LNCaP cells.". Toxicology in vitro : an international journal published in association with BIBRA 21 (3): 502–8. doi:10.1016/j.tiv.2006.10.016. PMID 17218080.
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Pharmacology: enzyme inhibition
|
|
| Class |
- Competitive inhibition
- Uncompetitive inhibition
- Non-competitive inhibition
- Suicide inhibition
- Mixed inhibition
|
|
| Substrate |
| Oxidoreductase (EC 1) |
- 1.1 Aldose reductase
- HMG-CoA reductase
- 1.5 Dihydrofolate reductase
- 1.17 Xanthine oxidase
- Ribonucleotide reductase
|
|
| Transferase (EC 2) |
- 2.1 COMT
- Thymidylate synthase
- 2.5 Dihydropteroate synthetase
- Farnesyltransferase
- 2.7 Nucleotidyltransferase
- Integrase
- Reverse transcriptase
- Protein kinase
|
|
| Hydrolase (EC 3) |
- 3.1 Phosphodiesterase
- Acetylcholinesterase
- Ribonuclease
- 3.2 Polygalacturonase
- Neuraminidase
- Alpha-glucosidase
- 3.4 Protease: Exopeptidase
- Dipeptidyl peptidase-4
- ACE
- Endopeptidase
- Trypsin
- Renin
- Matrix metalloproteinase
- 3.5 Histone deacetylase
- Beta-lactamase
|
|
| Lyase (EC 4) |
|
|
|
|
Drugs used in benign prostatic hyperplasia (G04C)
|
|
| 5α-reductase inhibitors |
|
|
| Alpha blockers (α1) |
- Alfuzosin
- Doxazosin
- Silodosin
- Tamsulosin
- Terazosin
|
|
| Herbals |
- Pygeum africanum
- Saw palmetto extract
|
|
| Other |
|
|
|
Index of reproductive medicine
|
|
| Description |
- Anatomy
- Physiology
- Development
- sex determination and differentiation
|
|
| Disease |
- Infections
- Congenital
- Neoplasms and cancer
- male
- female
- gonadal
- germ cell
- Other
- Symptoms and signs
|
|
| Treatment |
- Procedures
- Drugs
- benign prostatic hypertrophy
- erectile dysfunction and premature ejaculation
- sexual dysfunction
- infection
- hormones
- androgens
- estrogens
- progestogens
- GnRH
- prolactin
- Assisted reproduction
- Birth control
|
|
|
|
Acne-treating agents (D10)
|
|
| Antibacterial |
- Azelaic acid
- Benzoyl peroxide#
- 8-Hydroxyquinoline
- Blue light therapy
- Tea tree oil
|
|
| Keratolytic |
- Glycolic acid
- Salicylic acid#
- Sulfur
- Benzoyl peroxide#
|
|
| Anti-inflammatory |
- Nicotinamide
- Ibuprofen #
- Aspirin #
- Red light therapy
|
|
| Antibiotics |
- Clindamycin
- Dapsone
- Erythromycin
- Sulfacetamide
- Tetracyclines (Lymecycline
- Minocycline
- Doxycycline)
|
|
| Hormonal |
- Antiandrogens
- Contraceptives
|
|
| Retinoids |
- Adapalene
- Isotretinoin
- Motretinide
- Tazarotene
- Tretinoin
|
|
| Other |
- Benzamycin
- Epristeride
- Mesulfen
- Pelretin
- Stridex
- Tioxolone
|
|
| Combinations |
- Adapalene/benzoyl peroxide
- Benzoyl peroxide/clindamycin
- Clindamycin/tretinoin
- Erythromycin/isotretinoin
- Sulfacetamide/sulfur
|
|
-
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
|
|
|
Index of skin appendages
|
|
| Description |
- Anatomy
- Physiology
- Development
|
|
| Disease |
- Congenital
- Neoplasms and cancer
- Other
- Symptoms and signs
|
|
| Treatment |
|
|
|
|
Other dermatological preparations (D11)
|
|
| Medicated shampoos |
- Cetrimide
- Cadmium compounds
- Ketoconazole
- Povidone-iodine
- Selenium compounds
- Sulfur compounds
- Xenysalate
|
|
| Other dermatologicals |
| Seborrhoeic dermatitis/dandruff |
- Lithium succinate
- Pyrithione zinc
|
|
| Skin whitening/depigmenting |
- Hydroquinone
- Mequinol
- Monobenzone
|
|
| Skin darkening/pigmenting |
- Afamelanotide
- Melanotan II
|
|
| Anti-inflammatory/Immunomodulators |
- Oxaceprol
- Gamolenic acid
- Pimecrolimus
- Tacrolimus
- Alitretinoin
|
|
| Baldness treatments |
- 5α-Reductase inhibitors
- Alfatradiol
- Finasteride
- Dutasteride
- Saw palmetto extract
- Antiandrogens
- Spironolactone
- Topilutamide (fluridil)
- Potassium channel openers
|
|
| Hair growth inhibitors |
- Eflornithine
- 5α-Reductase inhibitors
- Antiandrogens
- Spironolactone
- Cyproterone acetate
- Flutamide
- Bicalutamide
- Ketoconazole
|
|
| Other |
- Calcium gluconate
- Magnesium sulfate
- Tiratricol
|
|
|
|
Index of skin
|
|
| Description |
- Anatomy
- Physiology
- Development
|
|
| Disease |
- Infections
- Vesiculobullous
- Dermatitis and eczema
- Papulosquamous
- Urticaria and erythema
- Radiation-related
- Pigmentation
- Mucinoses
- Keratosis, ulcer, atrophy, and necrobiosis
- Vasculitis
- Fat
- Neutrophilic and eosinophilic
- Congenital
- Neoplasms and cancer
- nevi and melanomas
- epidermis
- dermis
- Symptoms and signs
- Terminology
|
|
| Treatment |
- Procedures
- Drugs
- antibiotics
- disinfectants
- emollients and protectives
- itch
- psoriasis
- other
- Wound and ulcer
|
|
Index of skin appendages
|
|
| Description |
- Anatomy
- Physiology
- Development
|
|
| Disease |
- Congenital
- Neoplasms and cancer
- Other
- Symptoms and signs
|
|
| Treatment |
|
|
|
|
Androgenics
|
|
Receptor
(ligands) |
|
AR
|
|
Agonists
|
|
|
|
Mixed (SARMs)
|
- AC-262,356
- Andarine
- BMS-564,929
- Enobosarm
- LGD-2226
- LGD-3303
- LGD-4033
- S-23
- S-40503
- TFM-4AS-1
|
|
|
Antagonists
|
- 3α-Hydroxytibolone
- 3β-Hydroxytibolone
- Abiraterone
- Abiraterone acetate
- ARN-509
- Benorterone
- Bicalutamide
- BMS-641,988
- BOMT
- Canrenoic acid
- Canrenone
- Chlormadinone acetate
- Cimetidine
- Cioteronel
- Cyproterone
- Cyproterone acetate
- Delanterone
- Dienogest
- Drospirenone
- Enzalutamide
- Epitestosterone
- Flutamide
- Galeterone
- Hydroxyflutamide
- Inocoterone
- Ketoconazole
- Megestrol acetate
- Metogest
- Mifepristone
- Nilutamide
- Nomegestrol
- Nordinone
- Norgestimate
- Osaterone
- Oxendolone
- PF-998425
- Potassium canrenoate
- R2956
- Rosterolone
- RU-58642
- RU-58841
- Spironolactone
- Topilutamide (fluridil)
- Topterone
- Zanoterone
|
|
|
|
| Enzyme |
|
Modulators
|
- 20,22-desmolase, 17α-hydroxylase/17,20-lyase, 3β-HSD, 17β-HSD, 5α-reductase, and aromatase) (see also Steroid hormone metabolism modulator)
|
|
|
| Others |
|
Precursors/prohormones
|
- Cholesterol
- 22R-Hydroxycholesterol
- 20α,22R-Dihydroxycholesterol
- Pregnenolone
- Pregnenolone sulfate
- 17-Hydroxypregnenolone
- Progesterone
- 17-Hydroxyprogesterone
- 11-Deoxycortisol (cortodoxone)
- DHEA
- DHEA sulfate
- 5-Androstenediol
- 4-Androstenedione
|
|
|
Indirect
|
- Antigonadotropins (e.g., estrogens, progestogens, prolactin)
- GnRH agonists (e,g, GnRH, leuprorelin)
- GnRH antagonists (e.g., cetrorelix)
- Gonadotropins (e.g., FSH, hCG, LH)
- Kisspeptin
- Plasma proteins (ABP, albumin, SHBG)
|
|
|
|
See also: Estrogenics • Glucocorticoids • Mineralocorticoids • Progestogenics
|
|