Semin Reprod Med 2004; 22(1): 61-78
DOI: 10.1055/s-2004-823028
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Aromatase Inhibitors in Ovulation Induction

Mohamed F. M. Mitwally1 , 2 , Robert F. Casper1
  • 1Reproductive Sciences Division, Department of Obstetrics and Gynecology, University of Toronto, and The Samuel Lununfeld Research Institute, Mount Sinai Hospital, Toronto, Canada
  • 2Department of Gynecology and Obstetrics, University at Buffalo, School of Medicine and Biomedical Sciences, State University of New York (SUNY), Buffalo, New York
Further Information

Publication History

Publication Date:
13 April 2004 (online)

The new third generation aromatase inhibitors are extremely potent and specific oral inhibitors of estrogen production. We reported the success of using aromatase inhibitors for induction of ovulation in World Health Organization (WHO) type II anovulatory patients. Promising pregnancy rates were associated with the use of aromatase inhibitors for induction of ovulation in these women. In addition, the use of aromatase inhibition in conjunction with gonadotropin injection was associated with a significant reduction in the gonadotropin dose required for optimum controlled ovarian hyperstimulation. We believe that these oral agents are efficient and safe and have many advantages compared with clomiphene citrate (CC). We propose that aromatase inhibitors will replace CC in the future as the new primary treatment for ovulation induction. In this review, we present an update on the use of aromatase inhibitors for induction of ovulation and we discuss several new areas of potential interest regarding the use of aromatase inhibitors, either alone or together with recombinant follicle-stimulating hormone (FSH) for infertility treatment. Further research in these areas may demonstrate an expanded role in assisted reproductive technologies.

REFERENCES

  • 1 Whiteford L M, Gonzalez L. Stigma: the hidden burden of infertility.  Soc Sci Med. 1995;  40 27-36
  • 2 Downey J, Yingling S, McKinney M, Husami N, Jewelewicz R, Maidman J. Mood disorders, psychiatric symptoms, and distress in women presenting for infertility evaluation.  Fertil Steril. 1989;  52 425-432
  • 3 Schroeder P. Infertility and the world outside.  Fertil Steril. 1988;  49 765-767
  • 4 Homburg R, Insler V. Ovulation induction in perspective.  Hum Reprod Update. 2002;  8 449-462
  • 5 Guzick D S, Carson S A, Coutifaris C et al.. Efficacy of superovulation and intrauterine insemination in the treatment of infertility.  N Engl J Med. 1999;  340 177-183
  • 6 Melis G B, Paoletti A M, Strigini F et al.. Pharmacologic induction of multiple follicular development improves the success rate of artificial insemination with husband's semen in couples with male-related or unexplained infertility.  Fertil Steril. 1987;  47 441-445
  • 7 Serhal P F, Katz M, Little V, Woronowski H. Unexplained infertility: the value of Pergonal superovulation combined with intrauterine insemination.  Fertil Steril. 1988;  49 602-606
  • 8 Melis G B, Strigini F, Mais V et al.. Critical reappraisal of the clinical effectiveness of different methods of assisted fertilization.  J Endocrinol Invest. 1990;  13 263-274
  • 9 Franks S. Polycystic ovary syndrome.  N Engl J Med. 1995;  333 853-861
  • 10 Gompel A, Mauvais-Jarvis P. Induction of ovulation with pulsatile GnRH in hypothalamic amenorrhoea.  Hum Reprod. 1988;  3 473-477
  • 11 Lin S G, Gu C X, Xu L et al.. Experience with bromocriptine for the treatment of female infertility due to hyperprolactinemia.  Chin Med J (Engl). 1991;  104 679-684
  • 12 The ESHRE Capri Workshop . Female infertility: treatment options for complicated cases.  Hum Reprod. 1997;  12 1191-1196
  • 13 Nestler J E, Stovall D, Akhter N, Iuorno M J, Jakubowicz M J. Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome.  Fertil Steril. 2002;  77 209-215
  • 14 Dunaif A, Scott D, Finegood D et al.. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in polycystic ovary syndrome.  J Clin Endocrinol Metab. 1996;  81 3299-3306
  • 15 Ehrmann D A, Schneider D J, Sobel B E et al.. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 1997;  82 2108-2116
  • 16 Hasegawa I, Murakawa H, Suzuki M, Yamamoto Y, Kurabayashi T, Tanaka K. Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome.  Fertil Steril. 1999;  71 323-327
  • 17 Mitwally M FM, Kuscu N K, Yalcinkaya T M. High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome.  Hum Reprod. 1999;  14 2700-2703
  • 18 Azziz R, Ehrmann D, Legro R S et al.. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind placebo-controlled trial.  J Clin Endocrinol Metab. 2001;  86 1626-1632
  • 19 Ghazeeri G C, Haas D, Ke R W, Barker L J, Kutteh W H. The use of rosiglitazone in ovulation induction in clomiphene-resistant obese women with polycystic ovary syndrome.  Fertil Steril. 2001;  76 S36-S37
  • 20 Mitwally M FM, Greenblatt E M, Casper R F. Rosiglitazone improves endocrine and reproductive performance in women with polycystic ovary syndrome PCOS who failed to respond to metformin.  Fertil Steril. 2001;  76 S206
  • 21 Cataldo N A, Abbasi F, McLaughlin T L, Fechner P Y, Reaven G M, Giudice L C. Rosiglitazone in insulin-resistant women with polycystic ovary syndrome PCOS: effects on ovarian function and metabolism.  Fertil Steril. 2002;  78 S36
  • 22 Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis.  Endocr Rev. 1997;  18 774-800
  • 23 Dunaif A, Segal K R, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, indepentent of obesity, in polycystic ovary syndrome.  Diabetes. 1989;  38 1165-1174
  • 24 Thyer A C, Brzyski R, Easton C, Schenken R. A comparison of the effect of metformin and rosiglitazone on insulin action and secretion in women with polycystic ovary syndrome.  Fertil Steril. 2002;  78 S105-S106
  • 25 Costello M F, Eden J A. A systematic review of the reproductive system effects of metformin in patients with polycystic ovary syndrome.  Fertil Steril. 2003;  79 1-13
  • 26 Cole P A, Robinson C H. Mechanism and inhibition of cytochrome P-450 aromatase.  J Med Chem. 1990;  33 2933-2944
  • 27 Akhtar M, Njar V CO, Wright J N. Mechanistic studies on aromatase and related C-C bond cleaving P-450 enzymes.  J Steroid Biochem Mol Biol. 1993;  44 375-387
  • 28 Santen R J, Manni A, Harvey H, Redmond C. Endocrine treatment of breast cancer in women.  Endocr Rev. 1990;  11 221-265
  • 29 Lonning P E. Aromatase inhibition for breast cancer treatment.  Acta Oncol. 1996;  35(suppl 5) 38-43
  • 30 Buzdar A, Howell A. Advances in aromatase inhibition: clinical efficacy and tolerability in the treatment of breast cancer.  Clin Cancer Res. 2001;  7 2620-2635
  • 31 Goss P E, Strasser K. Aromatase inhibitors.  J Clin Oncol. 2001;  19 881-894
  • 32 Brueggemeier R W. Aromatase inhibitors: mechanisms of steroidal inhibitors.  Breast Cancer Res Treat. 1994;  30 31-42
  • 33 Bossche H V, Moereels H, Koymans L MH. Aromatase inhibitors: mechanisms for non-steroidal inhibitors.  Breast Cancer Res Treat. 1994;  30 43-55
  • 34 Santen R J, Lipton A, Kendall J. Successful medical adrenalectomy with aminoglutethimide: role of altered drug metabolism.  JAMA. 1974;  230 1661-1665
  • 35 Lipton A, Santen R J. Medical adrenalectomy using aminoglutethimide and dexamethasone in advanced breast cancer.  Cancer. 1974;  33 503-512
  • 36 Newsome H H, Brown P N, Terz J J et al.. Medical and surgical adrenalectomy in patients with advanced breast carcinoma.  Cancer. 1977;  39 542-546
  • 37 Winer E P, Hudis C, Burstein H J et al.. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: Status Report 2002.  J Clin Oncol. 2002;  20 3317-3327
  • 38 Buzdar A, Jonat W, Howell A et al.. Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials.  J Clin Oncol. 1996;  14 2000-2011
  • 39 Marty M, Gershanovich M, Campos B et al.. AIs, a new potent, selective aromatase inhibitor superior to aminoglutethimide AG in postmenopausal women with advanced breast cancer previously treated with antioestrogens.  Proc Am Soc Clin Oncol. 1997;  16 156
  • 40 Bergh J, Bonneterre J, Houston S J et al.. Vorozole Rivizor versus aminoglutethimide AG in the treatment of postmenopausal breast cancer relapsing after tamoxifen.  Proc Am Soc Clin Oncol. 1997;  16 156
  • 41 Dowsett M, Lonning P E. Anastrozole-a new generation in aromatase inhibition: clinical pharmacology.  Oncology. 1997;  54 (suppl 2) 11-14
  • 42 Dranitsaris G, Leung P, Mather J, Oza A. Cost-utility analysis of second-line hormonal therapy in advanced breast cancer: a comparison of two aromatase inhibitors to megestrol acetate.  Anticancer Drugs. 2000;  11 591-601
  • 43 Sioufi A, Gauducheau N, Pineau V et al.. Absolute bioavailability of letrozole in healthy post-menopausal women.  Biopharm Drug Dispos. 1997;  18 779-789
  • 44 Sioufi A, Sandrenan N, Godbillon J et al.. Comparative bioavailability of letrozole under fed and fasting conditions in 12 healthy subjects after a 25 mg single oral administration.  Biopharm Drug Dispos. 1997;  18 489-497
  • 45 McNeilly A S. The control of FSH secretion.  Acta Endocrinol Suppl (Copenh). 1988;  288 31-40
  • 46 Kamat A, Hinshelwood M M, Murry B A, Mendelson C R. Mechanisms in tissue-specific regulation of estrogen biosynthesis in humans.  Trends Endocrinol Metab. 2002;  13 122-128
  • 47 Naftolin F, MacLusky N J. Aromatization hypothesis revisited. In: Serio M Differentiation: Basic and Clinical Aspects. New York; Raven Press 1984: 79-91
  • 48 Naftolin F, MacLusky N J, Leranth C Z, Sakamoto H S, García-Segura L M. The cellular effects of estrogens on neuroendocrine tissues.  J Steroid Biochem. 1988;  30 195-207
  • 49 Naftolin F. Brain aromatization of androgens.  J Reprod Med. 1994;  39 257-261
  • 50 Roberts V J, Barth S, El-Roeiy A, Yen S SC. Expression of inhibin/activin system messenger ribonucleic acids and proteins in ovarian follicles from women with polycystic ovarian syndrome.  J Clin Endocrinol Metab. 1994;  79 1434-1439
  • 51 Yamoto M, Minami S, Nakano R. Immunohistochemical localization of inhibin subunits in polycystic ovary.  J Clin Endocrinol Metab. 1993;  77 859-862
  • 52 Jaatinen T, Penttila T, Kaipia A, Ekfors T, Parvinen M, Toppari J. Expression of inhibin alpha, beta A and beta B messenger ribonucleic acids in the normal human ovary and in polycystic ovarian syndrome.  J Endocrinol. 1994;  143 127-137
  • 53 Anderson R A, Groome N P, Baird D T. Inhibin A and inhibin B in women with polycystic ovarian syndrome during treatment with FSH to induce mono-ovulation.  Clin Endocrinol (Oxf). 1998;  48 577-584
  • 54 Lockwood G M, Muttukrishna S, Groome N P, Matthews D R, Ledger W L. Mid-follicular phase pulses of inhibin B are absent in polycystic ovarian syndrome and are initiated by successful laparoscopic ovarian diathermy: a possible mechanism regulating emergence of the dominant follicle.  J Clin Endocrinol Metab. 1998;  83 1730-1735
  • 55 Weil S J, Vendola K, Zhou J et al.. Androgen receptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations.  J Clin Endocrinol Metab. 1998;  83 2479-2485
  • 56 Weil S, Vendola K, Zhou J, Bondy C A. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development.  J Clin Endocrinol Metab. 1999;  84 2951-2956
  • 57 Vendola K A, Zhou J, Adesanya O O, Weil S J, Bondy C A. Androgens stimulate early stages of follicular growth in the primate ovary.  J Clin Invest. 1998;  101 2622-2629
  • 58 Vendola K, Zhou J, Wang J, Famuyiwa O A, Bievre M, Bondy C A. Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary.  Biol Reprod. 1999;  61 353-357
  • 59 Adashi E. Intraovarian regulation the proposed role of insulin-like growth factors.  Ann N Y Acad Sci. 1993;  687 10-12
  • 60 Giudice L C. Insulin-like growth factors and ovarian follicular development.  Endocr Rev. 1992;  13 641-669
  • 61 Yen S SC, Laughlin G A, Morales A J. Interface between extra-and intra-ovarian factors in polycystic ovary syndrome PCOS.  Ann N Y Acad Sci. 1993;  687 98-111
  • 62 Agarwal S K, Judd H L, Magoffin D A. A mechanism for the suppression of estrogen production in polycystic ovary syndrome.  J Clin Endocrinol Metab. 1996;  81 3686-3691
  • 63 Jakimiuk A J, Weitsman S R, Brzechffa P R, Magoffin D A. Aromatase mRNA expression in individual follicles from polycystic ovaries.  Mol Hum Reprod. 1998;  4 1-8
  • 64 Yarden R I, Wilson M A, Chrysogelos S A. Estrogen suppression of EGFR expression in breast cancer cells: a possible mechanism to modulate growth.  J Cell Biochem. 2001;  81(suppl 36) 232-246
  • 65 McClelland R A, Barrow D, Madden T A et al.. Enhanced epidermal growth factor receptor signaling in MCF7 breast cancer cells after long-term culture in the presence of the pure antiestrogen ICI 182,780 Faslodex.  Endocrinology. 2001;  142 2776-2788
  • 66 Miller D L, el-Ashry D, Cheville A L, Liu Y, McLeskey S W, Kern F G. Emergence of MCF-7 cells overexpressing a transfected epidermal growth factor receptor EGFR under estrogen-depleted conditions: evidence for a role of EGFR in breast cancer growth and progression.  Cell Growth Differ. 1994;  5 1263-1274
  • 67 Nirmala P B, Thampan R V. Ubiquitination of the rat uterine estrogen receptor: dependence on estradiol.  Biochem Biophys Res Commun. 1995;  213 24-31
  • 68 Rosenfeld C R, Roy T, Cox B E. Mechanisms modulating estrogen-induced uterine vasodilation.  Vascul Pharmacol. 2002;  38 115-125
  • 69 Mitwally M FM, Casper R F. The use of an aromatase inhibitor for induction of ovulation in cases of clomiphene citrate failure (abstract).  Hum Reprod. 2000;  15 (suppl) 71
  • 70 Mitwally M FM, Casper R F. Aromatase inhibition: a novel method of ovulation induction in women with polycystic ovarian syndrome.  Reprod Technol. 2000;  10 244-247
  • 71 Mitwally M FM, Casper R F. The aromatase inhibitor, letrozole: a promising alternative for clomiphene citrate for induction of ovulation.  Fertil Steril. 2000;  74(suppl 1) S35
  • 72 Mitwally M FM, Casper R F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.  Fertil Steril. 2001;  75 305-309
  • 73 Mitwally M FM, Casper R F. Single dose administration of the aromatase inhibitor, letrozole: a simple and convenient effective method of ovulation induction.  Fertil Steril. 2001;  76(suppl 1) S94-S95
  • 74 Mitwally M FM, Casper R F. The aromatase inhibitor, letrozole, decreases FSH dose required for ovarian superovulation. In: Proceedings of the 46th Annual Meeting of the Canadian Fertility and Andrology Society September 2000 Newfoundland, Canada;
  • 75 Mitwally M FM, Casper R F. Aromatase inhibition decreases FSH dose needed during controlled ovarian hyperstimulation: a controlled prospective trial.  J Soc Gynecol Investig. 2001;  8 85A
  • 76 Mitwally M FM, Casper R F. Aromatase inhibition improves response to controlled ovarian hyperstimulation without the antiestrogenic effects of clomiphene citrate (abstract).  Hum Reprod. 2001;  16(suppl 1) 15 , O-034
  • 77 Mitwally M FM, Casper R F. Aromatase inhibition improves ovarian response to FSH: a potential option for low responders during ovarian stimulation.  Fertil Steril. 2001;  75(suppl 1) S8-S9
  • 78 Mitwally M FM, Casper R F. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders.  Fertil Steril. 2002;  77 776-780
  • 79 Sammour A, Biljan M M, Tan S L, Tulandi T. Prospective randomized trial comparing the effects of letrazole LE and clomiphene citrate CC on follicular development, endometrial thickness and pregnancy rate in patients undergoing super-ovulation prior to intrauterine insemination IUI.  Fertil Steril. 2001;  76(suppl 1) S110
  • 80 Biljan M M, Tan S L, Tulandi T. Prospective randomized trial comparing the effects of 25 and 50mg of letrozole LE on follicular development, endometrial thickness and pregnancy rate in patients undergoing super-ovulation.  Fertil Steril. 2002;  78(suppl 1) S55
  • 81 El Helw B, El Sadek M, Matar H, Fouad S, El Nomrosy K, Abbas H. Single dose letrozole versus clomiphene citrate for superovulation prior to intrauterine insemination: a prospective randomised study (abstract).  Hum Reprod. 2002;  17 (suppl) 75 , O-209
  • 82 Healey S, Sylvestre C, Tan S L, Tulandi T, Biljan M. A comparison between superovulation with FSH and a combination of FSH and letrozole.  Fertil Steril. 2002;  78(suppl 1) S55-S56
  • 83 Prapas G, Pistofidis M, Tika M, Pelekanos M. Experience with the use of an aromatase inhibitor letrozolein patients with a history of poor ovarian responce in previous assisted reproduction cycles (abstract).  Hum Reprod. 2002;  17 (suppl) 75 , O-098
  • 84 Schoolcraft W, Surrey E, Minjarez D, Gardner D K. Antagonist/letrozole protocol for patients failing microdose agonist flare stimulation.  Fertil Steril. 2002;  78(suppl 1) S234
  • 85 Al-Omari W R, Al-Hadithi N, Sulaiman W R, Izat B. Comparison of two aromatase inhibitors in clomiphene resistant PCOS (abstract).  Hum Reprod. 2002;  17 (suppl) 75 , O-243
  • 86 Krasnopolskaya K, Kaluina A. Application of aromatase inhibitors anastrosol in IVF program for the treatment of infertility associated with severe endometriosis (abstract).  Hum Reprod. 2002;  17(suppl) 75 , P-438
  • 87 Package insert of letrozole Femara®
  • 88 Package insert of anastrozole Arimidex®
  • 89 Bulun S E, Zeitoun K M, Takayama K, Sasano H. Estrogen biosynthesis in endometriosis: molecular basis and clinical relevance.  J Mol Endocrinol. 2000;  25 35-42
  • 90 Vignali M, Infantino M, Matrone R et al.. Endometriosis: novel etiopathogenetic concepts and clinical perspectives.  Fertil Steril. 2002;  78 665-678
  • 91 Fang Z, Yang S, Gurates B et al.. Genetic or enzymatic disruption of aromatase inhibits the growth of ectopic uterine tissue.  J Clin Endocrinol Metab. 2002;  87 3460-3466
  • 92 Santen R J. To block estrogen's synthesis or action: that is the question.  J Clin Endocrinol Metab. 2002;  87 3007-3012
  • 93 Bulun S E, Gurates B, Fang Z J et al.. Mechanisms of excessive estrogen formation in endometriosis.  J Reprod Immunol. 2002;  55 21-33
  • 94 Meinhardt U, Mullis P E. The aromatase cytochrome P-450 and its clinical impact.  Horm Res. 2002;  57 145-152
  • 95 Yang S, Fang Z, Suzuki T J et al.. Regulation of aromatase P450 expression in endometriotic and endometrial stromal cells by CCAAT/enhancer binding proteins C/EBPs: decreased C/EBPbeta in endometriosis is associated with overexpression of aromatase.  Clin Endocrinol Metab. 2002;  87 2336-2345
  • 96 Scarpellini F, Sbracia M, Lecchini S, Frigo G, Scarpellini L. Aromatase inhibitors in the treatment of severe endometriosis.  J Soc Gynecol Investig. 2003;  10(suppl 2) 402
  • 97 Bulun S E, Amsterdam L, Jobanputra S, Gentry W, Rubin S D. Treatment of endometriosis-related pelvic pain with a combination of an aromatase inhibitor (anastrozole) plus a combination oral contraceptive: a novel approach. Proceedings of the 85th Meeting of the Endocrine Society, June 19-22, 2003 Bethesda, MD; The Endocrine Society Press 2003
  • 98 Franks S, Adams J, Mason H, Polson D. Ovulatory disorders in women with polycystic ovary syndrome.  Clin Obstet Gynaecol. 1985;  12 605-632
  • 99 Hull M GR. The causes of infertility and relative effectiveness of treatment. In: Templeton AA, Drife JO Infertility. London; Springer-Verlag 1992: 33-62
  • 100 Kistner R. Induction of ovulation with clomiphene citrate clomid.  Obstet Gynecol Surv. 1965;  20 873-900
  • 101 Wysowski D E. Use of fertility drugs in the United States, 1979 through 1991.  Fertil Steril. 1993;  60 1096-1098
  • 102 Garcia J, Jones G S, Wentz A C. The use of clomiphene citrate.  Fertil Steril. 1977;  28 707-717
  • 103 Goldfarb A F, Morales A, Rakoff A E, Protos P. Critical review of 160 clomiphene-related pregnancies.  Obstet Gynecol. 1968;  31 342-345
  • 104 Randall J M, Templeton A. Cervical mucus score and in vitro sperm mucus interaction in spontaneous and clomiphene citrate cycles.  Fertil Steril. 1991;  56 465-468
  • 105 Gysler M, March C, Mishell Jr D J, Bailey E J. A decade's experience with an individualized clomiphene treatment regimen including its effects on the postcoital test.  Fertil Steril. 1982;  37 161-167
  • 106 Gelety T J, Buyalos R P. The effect of clomiphene citrate and menopausal gonadotropins on cervical mucus in ovulatory cycles.  Fertil Steril. 1993;  60 471-476
  • 107 Gonen Y, Casper R F. Sonographic determination of an adverse effect of clomiphene citrate on endometrial growth.  Hum Reprod. 1990;  5 670-674
  • 108 Nelson L M, Hershlag A, Kurl R S, Hall J L, Stillman R J. Clomiphene citrate directly impairs endometrial receptivity in the mouse.  Fertil Steril. 1990;  53 727-731
  • 109 Li T C, Warren M A, Murphy C, Sargeant S, Cooke I D. A prospective, randomised, cross-over study comparing the effects of clomiphene citrate and cyclofenil on endometrial morphology in the luteal phase of normal fertile women.  Br J Obstet Gynaecol. 1992;  99 1008-1013
  • 110 Mikkelson T J, Kroboth P D, Cameron W J, Dittert L W, Chungi V, Manberg P J. Single-dose pharmacokinetics of clomiphene citrate in normal volunteers.  Fertil Steril. 1986;  46 392-396
  • 111 Hsu C C, Kuo H C, Wang S T, Huang K E. Interference with uterine blood flow by clomiphene citrate in women with unexplained infertility.  Obstet Gynecol. 1995;  86 917-921
  • 112 Oktay K, Berkowitz P, Berkus M. Schenken RS, Brzyski RG. The re-incarnation of an old question clomid effect on oocyte and embryo?.  Fertil Steril. 2000;  74 422-423
  • 113 Branigan E F, Estes M A. Minimal stimulation IVF using clomiphene citrate and oral contraceptive pill pretreatment for LH suppression.  Fertil Steril. 2000;  73 587-590
  • 114 Zayed F. Outcome of stimulated in vitro fertilisation SIVF using clomiphene citrate and human menopausal gonadotropin in different infertility groups.  Clin Exp Obstet Gynecol. 1999;  26 227-279
  • 115 Schmidt G E, Kim M H, Mansour R, Torello L, Friedman C I. The effects of enclomiphene and zuclomiphene citrates on mouse embryos fertilized in vitro and in vivo.  Am J Obstet Gynecol. 1986;  154 727-736
  • 116 Yoshimura Y, Hosoi Y, Atlas S J, Wallach E E. Effect of clomiphene citrate on in vitro ovulated ova.  Fertil Steril. 1986;  45 800-804
  • 117 London S N, Young D, Caldito G, Mailhes J B. Clomiphene citrate-induced perturbations during meiotic maturation and cytogenetic abnormalities in mouse oocytes in vivo and in vitro.  Fertil Steril. 2000;  73 620-626
  • 118 Hammond M, Halme J, Talbert L. Factors affecting the pregnancy rate in clomiphene citrate induction of ovulation.  Obstet Gynecol. 1983;  62 196-202
  • 119 Carpenter S E. Implantation. In: Wallach EE, Zacur HA Reproductive Medicine and Surgery. St Louis; Mosby 1995: 158-165
  • 120 Fritz M A, Holmes R T, Keenan E J. Effect of clomiphene citrate treatment on endometrial estrogen and progesterone receptor induction in women.  Am J Obstet Gynecol. 1991;  165 177-185
  • 121 Thatcher S S, Donachie K M, Glasier A, Hillier S G, Baird D T. The effects of clomiphene citrate on the histology of human endometrium in regularly cycling women undergoing in vitro fertilization.  Fertil Steril. 1988;  49 296-301
  • 122 Yeko T R, Nicosia S M, Maroulis G B, Bardawil W A, Dawood M Y. Histology of midluteal corpus luteum and endometrium from clomiphene citrate-induced cycles.  Fertil Steril. 1992;  57 28-32
  • 123 Sereepapong W, Triratanachat S, Sampatanukul P, Pruksananonda K, Boonkasemsanti K, Reinprayoon D. Effects of clomiphene citrate on the endometrium of regularly cycling women.  Fertil Steril. 2000;  73 287-291
  • 124 Yagel S, Ben-Chetrit A, Anteby E, Zacut D, Hochner-Celnikier D, Ron M. The effect of ethinyl estradiol on endometrial thickness and uterine volume during ovulation induction by clomiphene citrate.  Fertil Steril. 1992;  57 33-36
  • 125 Shimoya K, Tomiyama K, Hashimoto K et al.. Endometrial development was improved by transdermal estradiol in patients treated with clomiphene citrate.  Gynecol Obstet Invest. 1999;  47 251-254
  • 126 Gerli S, Gholami H, Manna A, Di Frega D, Vitiello C, Unfer V. Use of ethinyl estradiol to reverse the antiestrogenic effects of clomiphene citrate in patients undergoing intrauterine insemination: a comparative, randomized study.  Fertil Steril. 2000;  73 85-89
  • 127 Ben-Ami M, Geslevich Y, Matilsky M et al.. Exogenous estrogen therapy concurrent with clomiphene citrate: lack of effect on serum sex hormone levels and endometrial thickness.  Gynecol Obstet Invest. 1994;  37 180-182
  • 128 Bateman B G, Nunley Jr W C, Kolp L A. Exogenous estrogen therapy for treatment of clomiphene citrate-induced cervical mucus abnormalities: is it effective?.  Fertil Steril. 1990;  54 577-579
  • 129 Wu C H, Winkel C A. The effect of therapy initiation day on clomiphene citrate therapy.  Fertil Steril. 1989;  52 564-568
  • 130 Saleh A, Biljan M M, Tan S SSL, Tulandi T. Effects of tamoxifen Tx on endometrial thickness and pregnancy rates in women undergoing superovulation with clomiphene citrate CC and intrauterine insemination IUI.  Fertil Steril. 2000;  74(suppl 1) S90
  • 131 Boostanfar R, Jain J K, Paulson R J, Mishell Jr D R. A prospective randomized trial comparing clomiphene citrate with tamoxifen for ovulation induction in anovulatory women.  Fertil Steril. 2000;  74(suppl 1) S62
  • 132 Hurst B S, Tjaden B L, Kimball A, Schlaff W D, Damewood M D, Rock J A. Superovulation with or without intrauterine insemination for the treatment of infertility.  J Reprod Med. 1992;  37 237-239
  • 133 Ligibel J A, Winer E P. Clinical differences among the aromatase inhibitors.  Clin Cancer Res. 2003;  9 473S-479S
  • 134 Geisler J, Haynes B, Anker G, Dowsett M, Lonning P. Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study.  J Clin Oncol. 2002;  20 751-757
  • 135 Buzdar A, Howell A. Advances in aromatase inhibition: clinical efficacy and tolerability in the treatment of breast cancer.  Clin Cancer Res. 2001;  7 2620-2635
  • 136 Yates R, Dowsett M, Fisher G, Selen A, Wyld P. Arimidex ZD1033: a selective, potent inhibitor of aromatase in postmenopausal female volunteers.  Br J Cancer. 1996;  73 543-548
  • 137 Buzdar A U, Jones S E, Vogel C L, Wolter J, Plourde P, Webster A. A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Arimidex Study Group.  Cancer. 1997;  79 730-739
  • 138 Bisagni G, Cocconi G, Scaglione F, Fraschini F, Pfister C. Letrozole, a new oral non-steroidal aromatase inhibitor in treating postmenopausal patients with advanced breast cancer: a pilot study.  Ann Oncol. 1996;  7 99-102
  • 139 Buzdar A, Howell A. Advances in aromatase inhibition: clinical efficacy and tolerability in the treatment of breast cancer.  Clin Cancer Res. 2001;  7 2620-2635
  • 140 Hamilton A, Piccart M. The third-generation nonsteroidal aromatase inhibitors: a review of their clinical benefits in the second-line hormonal treatment of advanced breast cancer.  Ann Oncol. 1999;  10 377-384
  • 141 Goss P E. Risks versus benefits in the clinical application of aromatase inhibitors.  Endocr Relat Cancer. 1999;  6 325-332
  • 142 Palter S F, Tavares A B, Hourvitz A, Veldhuis J D, Adashi E Y. Are estrogens of import to primate/human ovarian folliculogenesis?.  Endocr Rev. 2001;  22 389-424
  • 143 Yanase T, Simpson E R, Waterman M. 17α-hydroxylase/17,20-lyase deficiency: from clinical investigation to molecular definition.  Endocr Rev. 1991;  12 91-108
  • 144 Mallin S R. Congenital adrenal hyperplasia secondary to 17-hydroxylase deficiency: two sisters with amenorrhea, hypokalemia, hypertension and cystic ovaries.  Ann Intern Med. 1969;  70 69-75
  • 145 Araki S, Chikazawa K, Sekiguchi I, Yamauchi H, Motoyama M, Tamada T. Arrest of follicular development in a patient with 17-hydroxylase deficiency folliculogenesis in association with a lack of estrogen synthesis in the ovaries.  Fertil Steril. 1987;  47 169-172
  • 146 Nagamani M, Dinh T V. 17-Hydroxylase deficiency in genetic females A report of two cases.  J Reprod Med. 1986;  31 734-738
  • 147 Roger M, Merceron R E, Girard F et al.. Dexamethasone-suppressible hypercorticosteronism in two 46,XX subjects with ambiguous genitalia and ovarian cysts: partial defect of 17 alpha-hydroxyase or 17,20-desmolase.  Horm Res. 1982;  16 23-31
  • 148 Rabinovici J, Blankstein J, Goldman B et al.. IVF and primary embryonic cleavage are possible in 17-hydroxylase deficiency despite extremely low intrafollicular 17ß E2 .  J Clin Endocrinol Metab. 1989;  68 693-697
  • 149 Geier A, Lunenfeld B, Pariente C et al.. Estrogen receptor binding material in blood of patients following clomiphene citrate administration: determination by radioreceptor assay.  Fertil Steril. 1987;  47 778-784
  • 150 Pariente C, Rabinovici J, Lunenfeld B et al.. Steroid secretion by granulosa cells isolated from a woman with 17α-hydroxylase deficiency.  J Clin Endocrinol Metab. 1990;  71 984-987
  • 151 Zelinski-Wooten M B, Hess D L, Wolf D P, Stouffer R L. Steroid reduction during ovarian stimulation impairs oocyte fertilization, but not folliculogenesis, in rhesus monkeys.  Fertil Steril. 1994;  61 1147-1155
  • 152 Mannaerts B, Uilenbroek J, Schot P, DeLeeuw R. Folliculogenesis in hypophysectomized rats after treatment with recombinant human follicle-stimulating hormone.  Biol Reprod. 1994;  51 72-81
  • 153 Ito Y, Fisher C R, Conte F A, Grambach M M, Simpson E R. Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries.  Proc Natl Acad Sci USA. 1993;  90 11673-11677
  • 154 Conte F A, Grumbach M M, Ito Y, Fisher C R, Simpson E R. A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase P450arom.  J Clin Endocrinol Metab. 1994;  78 1287-1292
  • 155 Morishima A, Grumbach M M, Simpson E R, Fisher C, Quin K. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens.  J Clin Endocrinol Metab. 1995;  80 3689-3698
  • 156 Mullis P E, Yoshimura N, Kuhlmann B, Lippuner K, Jaeger P, Harada H. Aromatase deficiency in a female who is compound heterozygote for two new point mutations in the P450arom gene: impact of estrogens on hypergonadotropic hypogonadism, multicystic ovaries, and bone densitometry in childhood.  J Clin Endocrinol Metab. 1997;  82 1739-1745
  • 157 Bulun S E. Aromatase deficiency in women and men: would you have predicted the phenotypes?.  J Clin Endocrinol Metab. 1996;  81 867-871
  • 158 Couzinet B, Lestrat N, Brailly S, Forest M, Schaison G. Stimulation of ovarian follicular maturation with pure follicle-stimulating hormone in women with gonadotropin deficiency.  J Clin Endocrinol Metab. 1988;  66 552-556
  • 159 Schoot D CJM, Herjan J T, Bennink C et al.. Human recombinant FSH induced growth of preovulatory follicles without concomitant increase in androgen and estrogen biosynthesis in a woman with isolated GT deficiency.  J Clin Endocrinol Metab. 1992;  74 1471-1473
  • 160 Mannaerts B, Leeuw R, VanRavestein J G, Wezenbeek P, Schuurs A, Kloosterboer H. Comparative in vitro and in vivo studies on the biological characteristics of human recombinant follicle-stimulating hormone.  Endocrinology. 1991;  129 2623-2630
  • 161 Shoham Z, Mannaerts B, Insler V, Coelingh H B. Induction of follicular growth using recombinant human follicle-stimulating hormone in two volunteer women with hypogonadotropic hypogonadism.  Fertil Steril. 1993;  59 738-742
  • 162 Shoham Z, Balen A, Patel A, Jacobs H S. Results of ovulation induction using human menopausal gonadotropins or purified follicle-stimulating hormone in hypogonadotropic hypogonadism patients.  Fertil Steril. 1991;  56 1048-1053
  • 163 Zelinski-Wooten M B, Hess D L, Baughman W O, Molskness T A, Wolf D P, Stouffer R L. Administration of an aromatase inhibitor during the late follicular phase of gonadotropin-treated cycles in rhesus monkeys: effects on follicle development, oocyte maturation, and subsequent luteal function.  J Clin Endocrinol Metab. 1993;  76 988-995
  • 164 Selvaraj N, Shetty G, Vijayalakshmi K, Bhatnagar A S, Moudgal N R. Effect of blocking oegrogen synthesis with a new generation aromatase inhibitor CGS 16949A on follicular maturation induced by pregnant mare serum gonadotrophin in the immature rat.  J Endocrinol. 1994;  142 563-570
  • 165 Moudgal N R, Shetty G, Selvaraj N, Bhatnagar A S. Use of a specific aromatase inhibitor for determining whether there is a role for oestrogen in follicle/oocyte maturation, ovulation and preimplantation embryo development.  J Reprod Fertil Suppl. 1996;  50 69-81
  • 166 Shetty G, Krishnamurthy H, Krishnamurthy H N, Bhatnagar A S, Moudgal R N. Effect of estrogen deprivation on the reproductive physiology of male and female primates.  J Steroid Biochem Mol Biol. 1997;  61 157-166
  • 167 Paesi F JA. The effect of small doses of oestrogen on the ovary of the immature rat.  Acta Endocrinol Suppl (Copenh). 1952;  11 251-268
  • 168 Zelinski-Wooten M B, Hess D L, Wolf D P, Stouffer R L. Steroid reduction during ovarian stimulation impairs oocyte fertilization, but not folliculogenesis, in rhesus monkeys.  Fertil Steril. 1994;  61 1147-1155
  • 169 Wang X N, Greenwald G S. Human chorionic gonadotropin or human recombinant follicle-stimulating hormone FSH-induced ovulation and subsequent fertilization and early embryo development in hypophysectomized FSH-primed mice.  Endocrinology. 1993;  132 2009-2016
  • 170 Mitwally M FM, Casper R F. Pregnancy outcome after the use of an aromatase inhibitor for ovarian stimulation.  Fertil Steril. 2002;  78 S277-S278

Robert F CasperM.D. 

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