Enclomiphene, an estrogen receptor antagonist for the treatment of testosterone deficiency in men

IDrugs

Volumn 12, Issue 2, 2009, Pages 109-119

  Hill, S ^a   Arutchelvam, V ^a   Quinton, R ^a,b  

^a ROYAL VICTORIA INFIRMARY   (United Kingdom)

^b NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CLOMIFENE CITRATE; ENCLOMIFENE; ENCLOMIFENE CITRATE; GONADOTROPIN; TESTOSTERONE; TESTOSTERONE UNDECANOATE; ZUCLOMIFENE;

ANDROGEN DEFICIENCY; AREA UNDER THE CURVE; DRUG EFFICACY; DRUG INDICATION; DRUG METABOLISM; DRUG SAFETY; DRUG STRUCTURE; ESTROGEN BLOOD LEVEL; FOOD AND DRUG ADMINISTRATION; GLUCOSE BLOOD LEVEL; GONADOTROPIN BLOOD LEVEL; HEADACHE; HOT FLUSH; HUMAN; HYPOGONADISM; HYPOTHALAMUS HYPOPHYSIS GONAD SYSTEM; MAXIMUM PLASMA CONCENTRATION; METABOLIC SYNDROME X; NAUSEA; NEGATIVE FEEDBACK; NONHUMAN; OBESITY; OVARY TUMOR; REVIEW; SIDE EFFECT; SPERMATOGENESIS; STEREOISOMERISM; TESTIS; TESTIS SIZE; TESTOSTERONE BLOOD LEVEL; TESTOSTERONE RELEASE; TIME TO MAXIMUM PLASMA CONCENTRATION; VISUAL DISORDER; VOMITING; WORLD HEALTH ORGANIZATION;

ANIMALS; BLOOD GLUCOSE; CLINICAL TRIALS AS TOPIC; CLOMIPHENE; ESTROGEN ANTAGONISTS; HUMANS; HYPOGONADISM; MALE; SPERMATOGENESIS; TESTOSTERONE;

EID: 60049084613     PISSN: 13697056     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (91)

1. 300412 Basic guide to the mechanisms of antiestrogen action. MacGregor JI, Jordan VC PHARMACOL REV 1998 50 2 151-196
2. 347643 Effect of estrogen agonists and antagonists on induction of progesterone receptor in a rat hypothalamic cell line. Fitzpatrick SL, Berrodin TJ, Jenkins SF, Sindoni DM, Deecher DC, Frail DE ENDOCRINOLOGY 1999 140 9 3928-3937
3. 489229 Zonagen reports first quarter financial results. Zonagen Inc PRESS RELEASE 2003 May 12
4. 581223 Drug development pipeline: Nebido. Schering AG COMPANY COMMUNICATION 2005 January 24
5. 618325 Schering Korea: Company history. Schering AG COMPANY WORLD WIDE WEB SITE 2005 August 17
6. 648612 Zonagen's Androxal does not induce supra-normal testosterone levels Zonagen Inc PRESS RELEASE 2006 February 03
7. 664911 Zonagen reports first quarter 2006 financial results. Zonagen Inc PRESS RELEASE 2006 May 01
8. 675424 Androxal (oral enclomiphene citrate) raises free and total testosterone in hypogonadal men: Comparison with androgel 1%. Wiehle RD, Garcia WD, Willett MS, Podolski JS AM SOC REPROD MED 2004 60 October 19 Abs O-216
9. 839585 Repros provides update for regulatory program associated with Androxal development. Repros Therapeutics Inc PRESS RELEASE 2007 October 15
10. 849625 Repros Therapeutics Inc reports third quarter 2007 financial results and provides clinical development update Repros Therapeutics Inc PRESS RELEASE 2007 November 09
11. 850154 Enclomiphene (Androxal) raises testosterone in men with low or normal testosterone and provides a more normal daily rhythm. Wiehle RD, Podolski JS, van As A J ANDROL 2007 Suppl S 64-65 • This abstract of a phase i clinical trial reports pharmacodynamics in 13 men with low to normal testosterone levels treated with enclomiphene (25 mg/day po for 14 days). at day 15, all patients exhibited mean testosterone levels within the 'normal' range; a mean increase in serum testosterone from baseline of 297.5 ng/dl was recorded. at 4 weeks, testosterone levels had returned to baseline levels in all patients.
12. 892632 Effect of anastrozole on bone mineral density: 5-Year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. Eastell R, Adams JE, Coleman RE, Howell A, Hannon RA, Cuzick J, Mackey JR, Beckmann MW, Clack G J CLIN ONCOL 2008 26 7 1051-1057
13. 908480 Androxal (enclomiphene citrate) acts centrally on the hypothalamic-pituitary-gonadal axis to increase LH, FSH and testosterone in men with adult idiopathic hypogonadotrophic hypogonadism. Wiehle RD, van As A, Podolski JS J UROL 2008 179 4 Suppl 426
14. 921247 Repros Therapeutics Inc initiates a comparative phase 2b study of oral androxal as compared to topical testim examining effects on male fertility and testicular function. Repros Therapeutics Inc PRESS RELEASE 2008 June 30
15. 946487 Indevus and FDA agree on path forward for NEBIDO. Indevus Pharmaceuticals Inc PRESS RELEASE 2008 September 26
16. 952532 The molecular basis of gonadotropin-releasing hormone action. Conn PM ENDOCR REV 1986 7 1 3-10
17. 952535 Differential regulation of gonadotropin secretion by testosterone in the human male: Absence of a negative feedback effect of testosterone on follicle-stimulating hormone secretion. Hayes FJ, DeCruz S, Seminara SB, Boepple PA, Crowley WF Jr J CLIN ENDOCRINOL METAB 2001 86 1 53-58
18. 952541 Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K J CLIN ENDOCRINOL METAB 1995 80 12 3689-3698
19. 952548 Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. Anawalt BD, Bebb RA, Matsumoto AM, Groome NP, Illingworth PJ, McNeilly AS, Bremner WJ J CLIN ENDOCRINOL METAB 1996 81 9 3341-3345
20. 952564 Testosterone replacement therapy: Current trends and future directions. Nieschlag E, Behre HM, Bouchard P, Corrales JJ, Jones TH, Stalla GK, Webb SM, Wu FC HUM REPROD UPDATE 2004 10 5 409-419
21. 952570 Effects of aromatase inhibition in hypogonadal older men: A randomized, double-blind, placebo-controlled trial. Burnett-Bowie SA, Roupenian KC, Dere ME, Lee H, Leder BZ CLIN ENDOCRINOL (OXF) 2008 70 1 116-123
22. 952572 The effect of clomiphene citrate in male infertility. Mellinger RC, Thompson RJ FERTIL STERIL 1966 17 1 94-103
23. 952573 Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: Who does and who does not benefit. Guay AT, Jacobson J, Perez JB, Hodge MB, Velasquez E INTL J IMPOT RES 2003 15 3 156-165
24. 952574 Complete reversal of adult-onset isolated hypogonadotropic hypogonadism with clomiphene citrate. Ioannidou-Kadis S, Wright PJ, Neely RD, Quinton R FERTIL STERIL 2006 86 5 1513.e5-1513.e9
25. 952575 Select patients with hypogonadotropic hypogonadism may respond to clomiphene citrate. Whitten SJ, Nangia AK, Kolettis PN FERTIL STERIL 2006 86 6 1664-1668
26. 952585 Sex differences of endogenous sex hormones and risk of type 2 diabetes: A systematic review and meta-analysis. Ding EL, Song Y, Malik VS, Liu S JAMA-J AM MED ASSOC 2006 295 11 1288-1299
27. 952594 Leptin and androgens in male obesity: Evidence for leptin contribution to reduced androgen levels. Isidori AM, Caprio M, Strollo F J CLIN ENDOCRINOL METAB 1999 84 10 3673-3680
28. 952596 Frequent occurrence of hypogonadotrophic hypogonadism in type 2 diabetes. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P J CLIN ENDOCRINOL METAB 2004 89 11 5462-5468
29. 952597 Low serum testosterone and mortality in older men. Laughlin GA, Barrett-Connor E, Bergstrom J J CLIN ENDOCRINOL METAB 2008 93 1 68-75
30. 952603 Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men. Pitteloud N, Hardin M, Dwyer AA, Valassi E, Yialamas M, Elahi D, Hayes FJ J CLIN ENDOCRINOL METAB 2005 90 5 2636-2641
31. 952608 Development, pharmacology and clinical experience with clomiphene citrate. Dickey RP, Holtkamp DE HUM REPROD UPDATE 1996 2 6 483-506
32. 952611 Effects of enclomiphene on estradiol-induced changes in LH secretion in ewes. Gregg DW, Nett TM J ANIM SCI 1990 68 10 3293-3299
33. 952613 Clomiphene citrate: Mechanism(s) and site(s) of action - A hypothesis revisited. Adashi EY FERTIL STERIL 1984 42 3 331-334
34. 952614 The agonistic-antagonistic properties of clomiphene: A review. Clark JH, Markaverich BM PHARMACOL THERAPEUT 1981 15 3 467-519
35. 952615 Estrogenic and antiestrogenic effects of enclomiphene and zuclomiphene on gonadotropin secretion by ovine pituitary cells in culture. Huang ES, Miller WL ENDOCRINOLOGY 1983 112 2 442-448
36. 952616 The effect of clomiphene citrate and its Zu or En isomers on the reproductive system of the immature male rat. Weissenberg R, Dar Y, Lunenfeld B ANDROLOGIA 1992 24 3 161-165
37. 952641 The effects of testosterone on insulin sensitivity in male rats. Holmang A, Bjorntorp P ACTA PHYSIOL SCAND 1992 146 4 505-510
38. 952669 Insulin and leptin resistance with hyperleptinemia in mice lacking androgen receptor. Lin HY, Xu Q, Yeh S, Wang RS, Sparks JD, Chang C DIABETES 2005 54 6 1717-1725
39. 952670 Single-dose pharmacokinetics of clomiphene citrate in normal volunteers. Mikkelson TJ, Kroboth PD, Cameron WJ, Dittert LW, Chungi V, Manberg PJ FERTIL STERIL 1986 46 3 392-396
40. 952672 Pharmacokinetics of intravenous clomiphene isomers. Szutu M, Morgan DJ, McLeish M, Phillipou G, Blackman GL, Cox LW, Dollman W BR J CLIN PHARMAC 1989 27 5 639-640
41. 952674 CYP2D6 is primarily responsible for the metabolism of clomiphene. Ghobadi C, Gregory A, Crewe HK, Rostami-Hodjegan A, Lennard MS DRUG METAB PHARMACOKINET 2008 23 2 101-105
42. 952676 Rabbit liver microsomal metabolism of enclomiphene. Ruenitz PC DRUG METAB DISPOS 1981 9 5 456-460
43. 952687 Induction of ovulation with human gonadotropins and with clomiphene. Jones GS, De Moraes-Ruehsen M FERTIL STERIL 1965 16 4 461-484
44. 952690 Update on the safety and efficacy of clomifene citrate as a therapeutic agent. Asch RH, Greenblatt RB J REPROD MED 1976 17 3 175-180
45. 952699 Selective estrogen-receptor modulators - Mechanisms of action and application to clinical practice. Riggs BL, Hartmann LC N ENGL J MED 2003 348 7 618-629
46. 957987 Enclomiphene citrate (Androxal) decreases serum glucose in men with idiopathic hypogonadotrophic hypogonadism. van As A, Wiehle RD ANN MEET ENDOCRINE SOC 2008 June 14-18 Abs P3-641 •• Results from a phase IIb/III, placebo-controlled clinical trial in 199 men with adult-onset hypogonadism treated with enclomiphene (12.5 and 25 mg po, qd) or topical androgel (5 g) for 6 months demonstrated that enclomiphene reduced FPG in men with high glucose levels. The rate of responders (at least two decreases in FPG by ≥ 10 mg/dl in 6 months) was 84 and 57% with 12.5- and 25-mg doses of enclomiphene, respectively, 41% for androgel and 35% for placebo. The reduction in the 12.5-mg enclomiphene high-glucose group was statistically significant (p = 0.002) compared with both baseline and a lower glucose group at the same dose.
47. 958070 Hypogonadism in men with type 2 diabetes. Jones TH PRACT DIAB INT 2007 24 5 269-277
48. 958102 Oral enclomiphene raises total serum testosterone in baboons and hypogonadal men. Wiehle R, Rice K, Garcia W, Willett M, Podolski J INT CONG ENDOCRINOL 2004 12 Abs 369
49. 958108 WO2006019916: Trans-clomiphene for the treatment of benign prostate hypertrophy, prostate cancer, hypogonadism, elevated triglycerides and high cholesterol. Zonagen Inc WORLD PATENT 2006 February 23 •• World patent that includes data from a study of the effects of 12 days of treatment with clomiphene citrate, enclomiphene or zuclomiphene (all administered at 1.5 mg/kg/day) in baboons. Total serum testosterone was increased by enclomiphene (8-fold) and clomiphene citrate (5-fold), but reduced by zuclomiphene. There were no effects on the levels of lh or FSH. Efficacy results from a phase I/II clinical trial of enclomiphene (12.5, 25 or 50 mg/day po) compared with AndroGel (5 or 10 g/day) in 62 hypogonadal men were also reported. after 14 days, enclomiphene dose-dependently increased mean total and apparent free serum testosterone levels from baseline and was more effective than AndroGel. All doses of enclomiphene were associated with a total testosterone diurnal pattern following a morning peak, a midday trough and a rise overnight compared with a nearly flat pattern with AndroGel. Levels of DHT relative to total serum testosterone increased by a factor of > 1.5 for men on either dose of AndroGel compared with 0.83 with enclomiphene (50 mg/day).
50. 961521 Repros Therapeutics Inc reports third quarter 2008 financial results. Repros Therapeutics Inc PRESS RELEASE 2008 November 10
51. 961723 Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Belchetz PE, Plant TM, Nakai Y, Keogh EJ, Knobil E SCIENCE 1978 202 4368 631-633
52. 961727 Androgen deprivation therapy, insulin resistance, and cardiovascular mortality: An inconvenient truth. Basaria S J ANDROL 2008 29 5 534-539
53. 961730 Modulation of pulsatile gonadotropin secretion by testosterone in man. Matsumoto AM, Bremner WJ J CLIN ENDOCRINOL METAB 1984 58 4 609-614
54. 961736 Hormonal regulation of spermatogenesis and spermiogenesis. Sofikitis N, Giotitsas N, Tsounapi P, Baltogiannis D, Giannakis D, Pardalidis N J STEROID BIOCHEM MOL BIOL 2008 109 3-5 323-330
55. 961742 Follicle stimulating hormone, the Sertoli cell, and spermatogenesis. Means AR, Fakunding JL, Huckins C, Tindall DJ, Vitale R RECENT PROG HORM RES 1976 32 477-527
56. 961748 The decline in androgen levels in elderly men and its clinical and therapeutic implications. Kaufman JM, Vermeulen A ENDOCR REV 2005 26 6 833-876
57. 961754 Steroid 5-α-reductase deficiency in man: An inherited form of male pseudohermaphroditism. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE SCIENCE 1974 186 4170 1213-1215
58. 961758 Steroid 5-α-reductase 2 deficiency. Wilson JD, Griffin JE, Russell DW ENDOCR REV 1993 14 5 577-593
59. 961761 The androgen resistance syndromes: Steroid 5-α-reductase 2 deficiency, testicular feminization, and related disorders. Griffin JE, McPhaul MJ, Russell DW, Wilson JD METAB MOL BASES INHER DIS (EDS: SCRIVER CR, BEAUDET AL, SLY WS, VALLE D) 2001 Mcgraw-Hill, New York, NY, USA 8th ed 4117
60. 961765 Molecular analysis of 5-α-reductase type 2 gene in eight unrelated Egyptian children with suspected 5-α-reductase deficiency: Prevalence of the G34R mutation. Mazen I, Gad YZ, Hafez M, Sultan C, Lumbroso S CLIN ENDOCRINOL (oxf) 2003 58 5 627-631
61. 961779 Hypogonadism in alcoholic liver disease: Evidence for a double defect. Van Thiel DH, Lester R, Sherins RJ GASTROENTEROLOGY 1974 67 6 1188-1199
62. 961780 Long term effects of cyclophosphamide on testicular function. Watson AR, Rance CP, Bain J BR MED J (CLIN RES ED) 1985 291 6507 1457-1460
63. 961781 Effects of fractionated irradiation of endocrine aspects of testicular function. Shapiro E, Kinsella TJ, Makuch RW, Fraass BA, Glatstein E, Rosenberg SA, Sherins RJ J CLIN ONCOL 1985 3 9 1232-1239
64. 961782 Leydig cell dysfunction and gynaecomastia in adult males treated with alkylating agents. Friedman NM, Plymate SR CLIN ENDOCRINOL (OXF) 1980 12 6 553-556
65. 961980 Metabolism of testicular androgens. Wilson JD HANDBOOK PHYSIOLOGY. SECT 7: ENDOCRINOLOGY. VOL V. MALE REPROD SYST (EDS: GREEP RO, ASTWOOD EB) 1975 American Physiological Society, Washington, DC, USA 491-507
66. 961985 Chapter 1: Testosterone: An overview of biosynthesis, transport, metabolism and non-genomic actions. Rommerts FFG TESTOSTERONE: ACTION, DEFICIENCY, SUBSTITUTION (EDS: NIESCHLAG E, BEHRE HM) 2004 Springer Verlag, Berlin, Germany 3rd Edition 1-39
67. 961990 Adverse events associated with testosterone replacement in middle-aged and older men: A meta-analysis of randomized, placebo-controlled trials. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, Bhasin S J GERONTOL SER A BIOL SCI MED SCI 2005 60 11 1451-1457
68. 961994 Endogenous sex hormones and prostate cancer: A collaborative analysis of 18 prospective studies. Roddam AW, Allen NE, Appleby P, Key TJ, Dorgan JF, Albanes D, Taylor PR, Ferrucci L, Carter HB, Metter EJ, Chen C et al J NATL CANCER INST 2008 100 3 170-183
69. 962001 Male hormonal contraception: So near and yet so far. Liu PY, McLachlan RI J CLIN ENDOCRINOL METAB 2008 93 7 2474-2476
70. 962004 Self-administered subcutaneous human menopausal gonadotrophin for the stimulation of testicular growth and the initiation of spermatogenesis in hypogonadotrophic hypogonadism. Jones TH, Darne JF CLIN ENDOCRINOL (OXF) 1993 38 2 203-208
71. 962007 Diurnal rhythm of testosterone induced by human chorionic gonadotrophin (hCG) therapy in isolated hypogonadotrophic hypogonadism: A comparison between subcutaneous and intramuscular hCG administration. Jones TH, Darne JF, McGarrigle HH EUR J ENDOCRINOL 1994 131 2 173-178
72. 962017 Treatment of male infertility secondary to morbid obesity. Roth MY, Amory JK, Page ST NAT CLIN PRACT ENDOCRINOL METAB 2008 4 7 415-419
73. 962020 Effect of body weight on testosterone/estradiol ratio in oligozoospermic patients. Fejes I, Koloszar S, Zavaczki Z, Daru J, Szollosi J, Pal A ARCH ANDROL 2006 52 2 97-102
74. 962021 Aromatase inhibitors for male infertility. Raman JD, Schlegel PN J UROL 2002 167 2 Pt 1 624-629
75. 962362 Chapter 4: Primary hypogonadism. Hamda A, Bouloux PM OXFORD ENDOCRINOL LIBRARY: TESTOSTERONE DEFICIENCY MEN (EDS: JONES TH) 2008 Oxford University Press, Oxford, UK 37-49
76. 962364 Guidelines for the use of androgens in men. WHO Special Programme of Research, Development and Research Training in Human Reproduction WHO PROGRAM REPORT 1992 Geneva
77. 2 and DHT also increased with enclomiphene treatment.
78. 963174 Androxal (oral enclomiphene citrate) raises free and total testosterone in hypogonadal men: Comparison with AndroGel 1%. Repros Therapeutics Inc COMPANY PRESENTATION 2008 May 22
79. 963233 Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: The European Male Aging Study. Wu FC, Tajar A, Pye SR, Silman AJ, Finn JD, O'Neill TW, Bartfai G, Casanueva F, Forti G, Giwercman A, Huhtaniemi IT et al J CLIN ENDOCRINOL METAB 2008 93 2737-2745.
80. 963861 Chapter 5: Secondary hypogonadism. Quinton R OXFORD ENDOCRINOL LIBRARY: TESTOSTERONE DEFICIENCY MEN (EDS: JONES TH) 2008 Oxford University Press, Oxford, UK 49-61
81. 963863 Chapter II. Jockenhoeval F MALE HYPOGONADISM (EDS: JOCKENHOEVEL F, SCHUBERT M) 2004 Uni-Med Verlag AG, Bremen, Germany 50-59
82. 963864 Chapter II. Jockenhoeval F MALE HYPOGONADISM (EDS: JOCKENHOEVEL F, SCHUBERT M) 2004 Uni-Med Verlag AG, Bremen, Germany 68-61
83. 963866 Reversible hypogonadism and azoospermia as a result of anabolic-androgenic steroid use in a bodybuilder with personality disorder. A case report. Boyadjiev NP, Georgieva KN, Massaldjieva RI, Gueorguiev SI J SPORTS MED PHYS FITNESS 2000 40 3 271-274
84. 963868 Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse. Tan RS, Vasudevan D FERTIL STERIL 2003 79 1 203-205
85. 963869 Chapter 11: Obesity, metabolic syndrome, and diabetes. Jones TH OXFORD ENDOCRINOL LIBRARY: TESTOSTERONE DEFICIENCY MEN (EDS: JONES TH) 2008 Oxford University Press, Oxford, UK 107-120
86. 963878 Chapter 12: The heart and cardiovascular disease. Jones TH 2008 OXFORD ENDOCRINOL LIBRARY: TESTOSTERONE DEFICIENCY MEN (EDS: JONES TH) 2008 Oxford University Press, Oxford, UK 121-132
87. 963879 Guideline for male testosterone therapy: A European perspective. Wu FCW J CLIN ENDOCRINOL METAB 2007 92 2 418-419
88. 970655 Induction of puberty by pulsatile gonadotropin releasing hormone. Stanhope R, Brook CG, Pringle PJ, Adams J, Jacobs HS LANCET 1987 2 8558 552-555
89. 970658 Induction of puberty in men by long-term pulsatile administration of low-dose gonadotropin-releasing hormone. Hoffman AR, Crowley WF Jr N ENGL J MED 1982 307 20 1237-1241
90. 971116 Stereospecific synthesis of clomiphene and tamoxifen via stannylcupration of diphenylacetylene. Cummins CH SYNTH COMMUN 1995 25 24 4071-4079
91. 971120 Synthesis with α-heterosubstituted phosphonates. Part 13. Synthesis of trisubstituted vinyl chlorides. Crenshaw MD, Zimmer H J ORG CHEM 1993 48 16 2782-2784