The Diagnostic Value of Inhibin in Infertility Evaluation

The fertility patient is entitled to a rapid and accurate diagnosis, a realistic assessment of the prospects for achieving pregnancy, and the timely initiation of an appropriate and effective therapy. The evaluation of ovarian reserve prior to initiation of ovarian stimulation is an important aspect of the infertility work-up of a woman requiring assisted reproductive techniques (ARTs). The ability of the ovary to respond to gonadotropin stimulation by the recruitment of a cohort of follicles is central to the success of treatment such as in vitro fertilization and intracytoplasmic sperm injection. Ovarian dysfunction, often age related, is an increasingly common cause of subfertility, and hyper- and hypogonadotropic dysovulation as well as the commoner polycystic ovarian syndrome (PCOS) are frequently encountered in fertility clinic. In cases of male-factor infertility, an ability to identify an accurate serum marker of Sertoli cell function has enhanced the diagnostic process, as previous endocrine markers such as follicle-stimulating hormone and testosterone were poor correlates of spermatogenic potential. The identification, purification, and cloning of the members of the inhibin-activin superfamily and the subsequent development of sensitive and highly specific two-site enzyme-linked immunoassays for these polypeptide hormones have provided tentative answers to many of the outstanding questions concerning the regulation of the hypothalamo-pituitary-gonadal axis. Assessment of serum levels of inhibin B appears to offer useful prognostic information about ovulatory function and predictive information about response to treatment. During very early pregnancy, especially in the presence of complications associated with ART such as multiple gestation and ovarian hyperstimulation syndrome, measurement of maternal levels of inhibin A and pro-αC offers a noninvasive test that can aid the counseling and management of patients.

KEYWORDS

Inhibin and infertility evaluation - inhibin B and ovarian reserve - inhibin and ART - inhibin B and male-factor infertility - inhibin and fertility prognosis

REFERENCES

• 1 Gosden R G. Biology of Menopause. London; Academic Press 1985
• 2 Baker T G, Scrimgeour J B. Development of the gonads in anencephalic human fetuses. In: Coutts JRT Functional Morphology of the Human Ovary Lancaster, England; MTP Press 1981
• 3 Smyth C D, Miro F, Whitelaw P F, Howles C M, Hillier S G. Ovarian/thecal interstitial androgen synthesis is enhanced by a FSH-stimulated mechanism.  Endocrinology. 1993;  133 1532-1538
• 4 Smyth C D, Miro F, Howles C M, Hillier S G. Effect of LH on FSH-activated signalling in rat ovary.  Hum Reprod. 1995;  10 33-39
• 5 Groome N P, Illingworth P J, O’Brien M et al.. Measurement of dimeric inhibin-B throughout the human menstrual cycle.  J Clin Endocrinol Metab. 1996;  81 1401-1405
• 6 Welt C K, Martin K A, Taylor A E et al.. Frequency modulation of follicle-stimulating hormone (FSH) during the luteal-follicular transition: evidence for FSH control of inhibin B in normal women.  J Clin Endocrinol Metab. 1997;  82 2645-2652
• 7 Groome N P, Illingworth P J, O’Brien M et al.. Detection of dimeric inhibin throughout the human menstrual cycle by 2-site enzyme immunoassay.  Clin Endocrinol (Oxf). 1994;  40 717-723
• 8 Klein N A, Illingworth P J, Groome N P, McNeilly A S, Battaglia M R, Soules M R. Decreased inhibin B secretion is associated with the monotrophic FSH rise in older, ovulatory women: a study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles.  J Clin Endocrinol Metab. 1996;  81 2742-2745
• 9 Burger H G, Dudley E C, Hopper J L et al.. The endocrinology of the menopausal transition: a cross-sectional study of a population-based sample.  J Clin Endocrinol Metab. 1995;  80 3537-3545
• 10 Reame N E, Wyman T L, Phillips T J et al.. Net increase in stimulatory input resulting from a decrease in inhibin B and an increase in activin A may contribute in part to the rise in follicular phase follicle-stimulating hormone of aging cycling women.  J Clin Endocrinol Metab. 1998;  83 3302-3307
• 11 Soules M R, Battaglia D E, Klein N A. Inhibin and reproductive aging in women.  Maturitas. 1998;  30 193-204
• 12 Welt C K, McNicholl D J, Taylor A E et al.. Female reproductive aging is marked by decreased secretion of dimeric inhibin.  J Clin Endocrinol Metab. 1999;  84 105-111
• 13 Ala-Fossi S L, Maenpaa J, Blauer D et al.. Inhibin A and B in peri- and postmenopause.  Maturitas. 1998;  30 273-281
• 14 Santoro N, Tovaghol Adel B S, Skurnick J H. Decreased inhibin tone and increased activin A secretion characterize reproductive aging in women.  Fertil Steril. 1999;  71 658-662
• 15 Templeton A, Morris J K, Parslow W. Factors that affect outcome of in- vitro fertilisation treatment.  Lancet. 1996;  348 1402-1406
• 16 Sharif K, Elgendy M, Lashen H, Afnan M. Age and basal follicle stimulating hormone as predictors of in vitro fertilisation outcome.  Br J Obstet Gynaecol. 1998;  105 107-112
• 17 Van Rooij I J, Bancsi L F, Broekmans F J, Looman C W, Habbema J D, teVelde E R. Women older than 40 years of age and those with elevated FSH hormone levels differ in poor response rate and embryo quality in in-vitro fertilization.  Fertil Steril. 2003;  79 482-488
• 18 Lashen H, Ledger W, Lopez-Bernal A, Barlow D. Poor responders to ovulation induction: is proceeding to in-vitro fertilization worthwhile?.  Hum Reprod. 1999;  14 964-969
• 19 Abdalla H, Thum M Y. An elevated basal FSH reflects a quantitative rather than qualitative decline of the ovarian reserve.  Hum Reprod. 2004;  19 893-898
• 20 Lenton E A, de Kretser D M, Woodward A J, Robertson D M. Inhibin concentrations throughout the menstrual cycle of normal, infertile and older women compared with those during spontaneous conception cycles.  J Clin Endocrinol Metab. 1991;  73 1180-1190
• 21 Klein N A, Battaglia D E, Fujimoto V Y et al.. Reproductive aging: accelerated ovarian follicular development associated with a monotropic FSH rise in normal women.  J Clin Endocrinol Metab. 1996;  81 1038-1045
• 22 Danforth D R, Arbogast L K, Mroueh J et al.. Dimeric inhibin: a direct marker of ovarian aging.  Fertil Steril. 1998;  70 119-123
• 23 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
• 24 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
• 25 Reddi K, Wicking E J, Hillier S G, Baird D T. Bioactive and FSH and inhibin concentrations during ovulation induction in patients with polycystic ovarian disease.  J Endocrinol. 1989;  123(suppl) 26
• 26 Lambert-Messerlian G M, Hall J E, Sluss P M et al.. Relatively low levels of dimeric inhibin circulate in men and women with polycystic ovarian syndrome using a specific two-site ELISA.  J Clin Endocrinol Metab. 1994;  79 45-50
• 27 Yen S SC, Vela P, Rankin J. Inappropriate secretion of FSH and LH in polycystic ovarian disease.  J Clin Endocrinol Metab. 1970;  30 435-442
• 28 Lockwood G M. The role of inhibin in polycystic ovarian syndrome.  Hum Fertil (Camb). 2000;  3 86-92
• 29 Seifer D B, Lambert-Messerlian G, Gardiner A C, Blazer A S, Berk C A. Day 3 serum inhibin B is predictive of assisted reproductive technologies outcome.  Fertil Steril. 1997;  67 110-114
• 30 Lockwood G M, Muttukrishna S, Groome N P, Ledger W L. Predicting the unpredictable: inhibin B is prognostic of unexpected under and over response to gonadotrophin stimulation in IVF.  Fertil Steril (Suppl). 1997;  S90-S91
• 31 Seifer D B, Scott R T, Bergh P A et al.. Women with declining ovarian reserve may demonstrate a decrease in day 3 serum inhibin B before a rise in day 3 follicle stimulating hormone.  Fertil Steril. 1999;  72 63-65
• 32 Lockwood G M, Muttukrishna S, Ledger W L. Inhibins and activins in human ovulation, conception and pregnancy.  Hum Reprod Update. 1998;  4(3) 284-295
• 33 Penarrubia J, Balasch J, Fabregues F et al.. Day 5 serum inhibin B concentrations as predictors of ART outcome in cycles stimulated with GnRH agonist-gonadotrophin treatment.  Hum Reprod. 2000;  15 1499-1504
• 34 Lockwood G M, Ertl A, Groome N P. Low levels of inhibin B explain “unexplained” infertility. 17th World Congress on Fertility and Sterility, Melbourne 2001
• 35 Jenkins J M, Davies D W, Devonport H et al.. Comparison of “poor” responders with “good” responders using a standard buserelin/HMG regime for IVF.  Hum Reprod. 1991;  6 918-921
• 36 Van Rysselberge M, Puissant F, Barlow P et al.. Fertility prognosis in IVF treatment of patients with cancelled cycles.  Hum Reprod. 1989;  4 663-666
• 37 Cahill D J, Prosser C J, Wardle P G et al.. Relative influence of serum follicle stimulating hormone, age and other factors on ovarian response to gonadotrophin stimulation.  Br J Obstet Gynaecol. 1994;  101 999-1002
• 38 Mukherjee T, Copperman A B, Lapinski R et al.. An elevated day three follicle-stimulating hormone:luteinizing hormone ratio (FSH:LH) in the presence of a normal day 3 FSH predicts a poor response to controlled ovarian hyperstimulation.  Fertil Steril. 1996;  65 588-593
• 39 Van Santbrink E J, Hop W C, Van Dessel T J et al.. Decremental follicle-stimulating hormone and dominant follicle development during the normal menstrual cycle.  Fertil Steril. 1995;  64 37-43
• 40 Lockwood G M. The regulation of ovulation. In: O'Brien PMS The Yearbook of Obstetrics and Gynaecology. Vol 7 London; RCOG Press 1999: 175-182
• 41 Fanchin R, deZiegler D, Olivennes F et al.. Exogenous follicle stimulating hormone ovarian reserve test (EFORT): a simple and reliable screening test for detecting poor ‘responders’ in in-vitro fertilization.  Hum Reprod. 1994;  9 1607-1611
• 42 Kwee J, Elting M W, Schats R et al.. Comparison of endocrine tests with respect to their predictive value on the outcome of ovarian hyperstimulation in IVF treatment: results of a prospective randomized study.  Hum Reprod. 2003;  18 1422-1427
• 43 Gulekli B, Bulbul Y, Onvural A et al.. Accuracy of ovarian reserve tests.  Hum Reprod. 1999;  14 2822-2826
• 44 Popovic-Todorovic B, Loft A, Lindhard A et al.. A prospective study of predictive factors of ovarian response in ‘standard’ IVF/ICSI patients treated with recombinant FSH. A suggestion for a recombinant FSH dosage normogram.  Hum Reprod. 2003;  18 781-787
• 45 Yong P Y, Baird D T, Thong K J et al.. Prospective analysis of the relationships between the ovarian follicle cohort and basal FSH concentration, the inhibin response to exogenous FSH and ovarian follicle number at different stages of the normal menstrual cycle and after pituitary down-regulation.  Hum Reprod. 2003;  18 35-44
• 46 Hofmann G E, Danforth D R, Seifer D B. Inhibin-B: the physiologic basis of the clomiphene citrate challenge test for ovarian reserve screening.  Fertil Steril. 1998;  69 474-477
• 47 Elting M W, Kwee J, Schats R et al.. The rise of estradiol and inhibin B after acute stimulation with follicle-stimulating hormone predict the follicle cohort size in women with polycystic ovary syndrome, regularly menstruating women with polycystic ovaries, and regularly menstruating women with normal ovaries.  J Clin Endocrinol Metab. 2001;  86 1589-1595
• 48 Dzik A, Lambert-Messerlian G, Izzo V M et al.. Inhibin B response to EFORT is associated with the outcome of oocyte retrieval in the subsequent IVF cycle.  Fertil Steril. 2000;  74 1114-1117
• 49 Fawzy M, Lambert A, Harrison R F et al.. Day 5 inhibin B levels in a treatment cycle are predictive of IVF outcome.  Hum Reprod. 2002;  17 1535-1543
• 50 Lockwood G M, Muttukrishna S, Groome N P, Ledger W L. Circulating inhibins and activin A during GnRH-analogue down-regulation and ovarian hyperstimulation with recombinant FSH for in-vitro fertilization-embryo transfer.  Clin Endocrinol (Oxf). 1996;  45 741-748
• 51 McLachlan R I, Healy D L, Robertson D M, Burger H G, de Kretser D M. Circulating immunoreactive inhibin in the luteal phase and early gestation in women undergoing ovulation induction.  Fertil Steril. 1987;  48 1001-1005
• 52 Hughes E G, Tovertson D M, Handelsman D J, Hayward S, Healy D L, deKretser D M. Inhibin and estradiol responds to ovarian hyper stimulation: effects of age and predictive value for in vitro fertilization outcome.  J Clin Endocrinol Metab. 1990;  70 358-364
• 53 Eldar-Geva T, Robertson D M, Cahir N et al.. Relationship between inhibin A and inhibin B and ovarian follicle development after a daily fixed dose administration of recombinant FSH.  J Clin Endocrinol Metab. 2000;  85 607-613
• 54 Eldar-Geva T, Margalioth E J, Ben-Chetrit A et al.. Serum inhibin B levels measured during early FSH administration for IVF may be of value in predicting the number of oocytes to be retrieved in normal or low responders.  Hum Reprod. 2002;  17 2331-2337
• 55 Abe Y, Hasegawa Y, Miyamoto K et al.. High concentrations of plasma immunoreactive inhibin during normal pregnancy in women.  J Clin Endocrinol Metab. 1990;  71 133-137
• 56 Tabie T, Ochiai K, Terashima Y, Takanashi N. Serum levels of inhibin in maternal and umbilical blood during pregnancy.  Am J Obstet Gynecol. 1991;  164 896-900
• 57 Yohkaichiya T, Polson D, O’Connor A et al.. Concentrations of immunoreactive inhibin in serum during human pregnancy: evidence for an ovarian contribution.  Reprod Fertil Dev. 1991;  3 671-678
• 58 Baird D T, Smith K B. Inhibin and related peptides in the regulation of reproduction.  Oxf Rev Reprod Biol. 1993;  15 191-232
• 59 Tovanabutra S, Illingworth P J, Ledger W L et al.. The relationship between peripheral immunoactive inhibin, human chorionic gonadotrophin, oestradiol and progesterone during human pregnancy.  Clin Endocrinol (Oxf). 1993;  38 101-107
• 60 Muttukrishna S, George I, Fowler P A, Grome N P, Knight P G. Measurement of serum concentrations of inhibin A during human pregnancy.  Clin Endocrinol (Oxf). 1995;  42 391-397
• 61 Illingworth P J, Groome N P, Duncan W C et al.. Measurement of circulating inhibin forms during the establishment of pregnancy.  J Clin Endocrinol Metab. 1996;  81 1471-1475
• 62 Lockwood G M, Ledger W L, Barlow D H, Groome N P, Muttukrishna S. Measurement of inhibin and activin in early pregnancy: demonstration of fetoplacental origin and role in prediction of early-pregnancy outcome.  Biol Reprod. 1997;  57 1490-1494
• 63 Lockwood G M, Muttukrishna S, Groome N P, Ledger W L. Inhibin pro-alpha C and the prediction of OHSS in IVF treatment.  Fertil Steril. 1998;  70 S356
• 64 Ezeh U E, Moore H DM, Cooke I D. Correlation of testicular sperm extraction with morphological, biophysical and endocrine profiles in men with azoospermia due to primary gonadal failure.  Hum Reprod. 1998;  13 3066-3074
• 65 Lockwood G M. Inhibin B and the prediction of sperm yield with PESA/TESE. IFFS Congress, Sydney 1999
• 66 Bohring C, Schroeder-Printzen I, Weidner W et al.. Serum levels of inhibin B and follicle-stimulating hormone may predict successful sperm retrieval in men with azoospermia who are undergoing testicular sperm extraction.  Fertil Steril. 2002;  78 1195-1198
• 67 Pierik F H, Abdesselam S A, Vreeburg J T et al.. Increased serum B levels after varicocele treatment.  Clin Endocrinol (Oxf). 2001;  54 775-780