Luteal phase deficiency after completely normal follicular and periovulatory phases

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1 FERTILITY AND STERILITY Copyright" 1989 The Amerian Fertility Soiety Printed on aid-free paper in U.S.A. Luteal phase defiieny after ompletely normal folliular and periovulatory phases Larene Grunfeld, M.D.t Benjamin Sandler, M.D. Janis Fox, M.D. Cathy Boyd, R.N. Paul Kaplan, Ph.D. Daniel Navot, M.D. Mount Sinai Shool of Mediine, Department of Obstetris and Gyneology, Ne York, Ne York Luteal phase defet (LPD) aounts for a signifiant proportion of reprodutive disorders, hoever its etiology is still debated. A prospetive study as performed on 37 ovulatory omen to determine hether LPD an our in yles haraterized by ompletely normal folliulogenesis. Criteria for normal folliulogenesis inluded: a gradual rise of serum estradiol, a luteinizing hormone (LH) surge, the presene of a dominant follile that disappeared, an inrease of serum progesterone, and normal serum levels of prolatin, testosterone, dehydroepiandrosterone sulfate, follile-stimulating hormone, and LH. Thirty of 37 omen fulfilled the above mentioned strit riteria and underent endometrial biopsy in the late luteal phase. Seven of 30 (23%) demonstrated a delay in endometrial development and all had normal hormonal and ultrasonographi parameters of folliulogenesis and ovulation. Women ith delayed endometrial development demonstrated slightly longer folliular phases (17.0 ± 1.1 versus 14.5 ± 0.3 days). Perfetly normal folliular and periovulatory events may be folloed by defiient luteal phases. Fertil Steril52:919, 1989 Luteal phase defet (LPD) an be demonstrated in up to 20% of random yles here endometrial biopsies are performed. Approximately 5% of infertile omen and 30% of omen ith habitual abortion ill demonstrate a delay in endometrial development on repeated biopsies. I - 3 Luteal phase defet is also more ommon in omen over age 35, those ith hyperprolatinemia, or on ovulation indution therapy. 4 While LPD is idely reognized as a ause of implantation failure its etiology is still debated. Possible explanations for LPD inlude inadequate orpus luteum steroid prodution or defetive endometrial responsiveness to progesterone (P) seretion. Evidene for an end-organ defet as the etiology for LPD inludes the demonstration of Reeived May 25, 1989; revised and aepted August 24, * Presented in part at the 36th Annual Meeting of the Soiety for Gyneologial Investigation, San Diego, California, Marh 15 to 18, t Reprint requests: Larene Grunfeld, M_D_, Mount Sinai Shool of Mediine, Box 1175, Ne York, Ne York LPD in the presene of normal serum P.5.6 A derease in P reeptor in the endometrium of omen ith LPD has been desribed. 7 Other investigators ould not onfirm these findings and ould only demonstrate a derease in endometrial Preeptor ativity in the folliular phase. 8 Evidene for the role of folliular events as the determinants of orpus luteum funtion has been provided by primate studies of DiZerega and Hodgen4 and Stouffer et a1. 9 In these experiments folliular phase manipulation resulted in altered orpus luteum development. Also in support of aberrant folliulogenesis as a soure for LPD is the observation of a high inidene of yles ith signifiantly abnormal serum estradiol (E 2) and dereased follile size in patients ith LPD. 10 These findings demonstrate that abnormal folliulogenesis is assoiated ith a high inidene of luteal phase defiieny. The potential for normal folliulogenesis to result in LPD is not, hoever, knon. To further expand our knoledge of the etiology of luteal phase defets, the presene of a delay in endometrial development as prospe- Grunfeld et al. LPD after normal folliulogenesis 919

2 tively investigated in yles here the folliular and periovulatory phases ere normal by strit definition. MATERIALS AND METHODS Thirty-seven patients ere reruited for this study from those enrolled in the in vitro fertilization program (IVF) at Mount Sinai Medial Center beteen January 1, 1988 to February 1, This group onsisted of 37 onseutive patients ho had exess embryos ryopreserved. The auses of infertility inluded tubal disease (n = 28), male fator (n = 6), or immunologi infertility (n = 3). Patients' ages ranged from 28 to 40 and 19 patients ere older than 35 years. All patients had regular menses. None had evidene of hyperprolatinemia, thyroid dysfuntion, a previous history of more than one spontaneous abortion, hyperandrogenism, or elevated gonadotropins (luteinizing hormone [LH] < 25, follile-stimulating hormone [FSH] < 25, and LH/FSH < 2). Patients signed informed onsent and appropriate approval as obtained from the Institutional Revie Board. Patients underent endometrial sampling in natural yles here the folliular phases ere losely srutinized. Daily measurements of serum E 2, P, LH, FSH, and ultrasound examinations ere begun 10 days after menses. Monitoring as ontinued until at least 2 days after the detetion of an LH surge. An LH surge as defined by either a fivefold inrease over the mean of three previous LH values or an LH exeeding 50 miu /ml. Cyles ere normalized to the day of highest serum LH (day 0). Prolatin (PRL), dehydroepiandrosterone sulfate (DHEA S), and testosterone (T) ere measured in the midfolliular periods. Early folliular (menstrual) levels of FSH, LH, and E2 ere also assessed on these patients. Ultrasound examination of the dominant follile as performed ith a 5.0 mhz vaginal ultrasound transduer, Ultramark IV (Advaned Tehnial Laboratory, In. Bothell, WA). Serum E 2, P, LH, FSH, PRL, DHEA-S, and T ere performed by radioimmunoassay (RIA) double antibody (Diagnosti Produts, Los Angeles, CAl. The loest detetable level for E 2, P, LH, FSH, PRL, DHEA-S, and T ere 8 pg/ml, 0.05 ng/ml, 2.0 miu /ml, 1.2 miu/ml, 1.4 ng/ml, 2.1 ILg/dL, and 4 ng/dl, respetively. The intra -assay and interassay variability ere 4.2% and 5.1% for E 2, 5.9% and 6.6% for P, 2.3% and 5.9% for LH, 4.5% and 5.8% for 920 Grunfeld et al. LP D after normal folliulogenesis FSH, 3.2% and 7.5% for PRL, 4.9% and 5.2% for DHEA-S, and 9.5% and 10.8% for T. Only patients that met riteria for normal folliulogenesis ll ere inluded in the data analysis. Evidene for normal folliulogenesis inluded: (1) a gradual rise of serum E2 surpassing a threshold value of 200 pg/ml at or a day before the LH surge (day 0), (2) a serum LH surge of more than 5X the mean of preeding values or more than 50 miu / ml, (3) the presene of a dominant follile that attained a diameter of ~18 mm and either disappeared or dereased in size by day +2, (4) a doubling of serum P from day -1 to + 1, and (5) normal folliular phase levels ofprl «15 ng/ml), T «80 ng/dl), DHEA-S «340 ILg/dL), FSH and LH < 25 miu /ml, and LHjFSH < 2. Endometrial biopsies ere performed late in the luteal phase. Endometrial dating as performed by a gyneologial pathologist and one of the investigators (DN), both of hom ere blinded to the linial situation. The histologial dating as ompared ith the hronologial dating alulated both prospetively from the onset of the LH surge (day 0) and retrospetively from the onset of the next menses (luteal day 14). Cyles here the endometrial dating lagged more than 2 days from the hronologial dating alulated either retrospetively or prospetively ere lassified as LPD. Cyles here endometrial dating orresponded ithin 2 days of the hronologial dating ere onsidered normal. Statistial analysis as performed using analysis of variane. Levels of signifiane ere set at P < Values are presented as means ± standard error (SE). RESULTS Thirty-seven patients underent folliular phase monitoring as outlined above. Seven patients failed to meet strit riteria for normal folliulogenesis and ere exluded from data analysis. Normal folliular phases ere identified in the 30 remaining patients and these subjets underent endometrial sampling in the late luteal phase. Endometrial dating as performed both prospetively from the onset of the LH surge (day 0) and retrospetively from the onset of the next menses. Five ofthe 30 (20%) demonstrated endometrial histology that lagged more than 2 days from their hronologial date hen dating as alulated prospetively from day o. An additional to patients (23 %) hose endometrium as lassified as normal Fertility and Sterility

3 Table 1 Cyle Charateristis and the Inidene of LPD Aording to Prospetive (LH Surge) versus Retrospetive (Next Menstrual Period) Chronologial Dating a Prospetive dating Retrospetive dating In phase LPD In phase LPD No. of omen %b Age (y) Endometrial lag (d) Luteal phase length (d) Folliular phase length (d) 25 (83) 35.3±0.8 O.O±O ± ± 0.3' 5 (17) 36.4 ± ± ± ± (76) 34.8± ±O.4 d 13.9 ± ± (24) 36.7 ± ± 0.6" 12.8 ± ± 1.4 a Values are means ± SE. b Values in parentheses are perents. LPD versus in phase, P < d LPD versus in phase, P < "LPD prospetive dating versus LPD retrospetive dating, not signifiant., LPD versus in phase, P < by prospetive dating had out of phase endometrial biopsies hen dating as performed retrospetively (from the next menses). Luteal phase defet as never diagnosed by prospetive dating hen the retrospetive dating ould have onsidered the biopsy in phase. In 9 of the 30 (30%) ases the prospetive dating as loser to the histologi dating hile in 4 (13%), the date alulated retrospetively from the next menses as loser to the histologi date. All of these subjets and the remaining 17 ases ere assoiated ith normal luteal phases (median 14, range 10 to 16).12 The lag in development as signifiant ith a mean delay of 4.1 ± 0.3 days (dating prospetively) and 3.6 ± 0.4 (dating retrospetively). The folliular phase lengths ere slightly longer in yles ith LPD, hen the alulation as performed using prospetive dating (P < 0.05, Table 1). In Table 1 age and yle harateristis are detailed. Evidene for ompletely normal folliulogenesis in the study population is given in Figure 1. No signifiant differene as deteted in E2, P, FSH, LH, or follile maturation beteen normal and LPD yles. In addition to the above mentioned parameters serum PRL, T, and DHEA-S ere measured in the midfolliular periods. Mean serum PRL as 12.3 ± 1.3 ng/ml, Tas 30 ± 4.7 ng/dl, and DHEA-S as ± 24.3 ~g/dl. Early folliular (menstrual) levels of FSH, LH, and E2, hih may be relevant for normal folliulogenesis, ere also assessed on these patients. Menstrual E2 levels ere onsistently belo 75 pg/ml (mean = 44.8 ± 4.8 pg/ml), FSH as 12.5 ± 1.2 miu/ml, and LH as 9.3 ± 1.8 miu/ml. DISCUSSION We have identified seven ases of luteal phase defets that ourred in yles that ere flaless in their folliular development. In this selet population of omen ith doumented normal folliular phases the inidene of delayed endometrial development as 23 %. Although this finding is similar to the frequeny of abnormal biopsies demonstrated by other authors in normal omen,1,3 the oexistene of perfetly normal folliulogenesis and periovulatory events ith subsequent abnormal endometrial biopsies has never been demonstrated. Prospetive dating of endometrial biopsies for this study as performed by arefully doumenting the serum LH surge. In most ases, the prospetive date agreed ith the date using the more traditional method of ounting bakards from the onset of the next menses. In only to ases as there a disrepany here the traditional method ould have diagnosed LPD and the prospetive dating found the endometrium to be in phase. All ases of LPD diagnosed in this study ould have been onsidered abnormal using retrospetive dating. Noyes et al.,13 in their original study, used retrospetive dating and assumed a 14 day luteal phase beause there as no better means to aurately date periovulatory events. When the luteal phase duration is 14 days, retrospetive dating must orrespond to prospetive dating. Hoever, hen the luteal phase duration is <14 days retrospetive dating tends to overdiagnose LPD and prospetive dating more aurately orresponds to the sequene of endometrial maturation. The greater auray of prospetive dating has been suggested by Li et aly In our study, prospetive dating resulted in greater similarity beteen histologi and hronologi dating. The patients in this study ere all seleted for normaly of their folliular phase events as deteted by an LH surge, a preovulatory peak in se- Grunfeld et al. LPD after normal folliulogenesis 921

4 A B C E NO_L(nd3) LPo... n - NO_L(n=Z.) -- NO_L(nd.) a:: LPo... n I- ~ f 300 ;:) f s! :::E a::... l- U ~ en 40 ::::i...! z :z: 80 is 20 I a:: ;:) C ()o CYCLE DAY CYCLE DAY CYCLE DAY Iii a::! ~ W Do. 20 :z:,f I, W 0 en... Figure 1 (A) Periovulatory E2 and P serum levels are demonstrated (mean ± SE). Serum estradiol and P levels did not signifiantly differ beteen patients demonstrating LPD or normal biopsies on any yle day. (B) Periovulatory LH and FSH serum levels are demonstrated (mean ± SE). Both LH and FSH surges are detetable in all yles. There is no signifiant differene in serum LH or FSH beteen patients demonstrating LPD or normal biopsies on any yle day. (C) Transvaginal ultrasound measurements of the dominant follile are demonstrated (mean ± SE). No differene is demonstrated in the size of the leading follile beteen patients demonstrating LPD or normal biopsies. rum E 2, an early rise in P, and the disappearane of a dominant follile. We have deided to orrelate folliular and periovulatory events ith endometrial biopsy as opposed to luteal phase P seretion. Progesterone has been shon to be an inaurate measure of luteal funtion ith onsiderable overlap beteen normal and LPD yles. I5 To avoid ontroversy e have used endometrial dating only as the sine qua non of luteal funtion. In ontrast to the lassial definition of LPD requiring to out of phase endometrial biopsies only a single yle as studied in these patients. Thus no onlusion are attempted regarding the repetitive nature of the observed endometrial abnormality. The finding of abnormal luteal phases in yles haraterized by normal folliulogenesis has important physiologial as ell as linial impliations. Luteal phase adequay is assumed based on normal folliular development in some linial situation here endometrial biopsies are not desired, suh as the replaement of ryopreserved embryos, donated embryos, or hen deisions must be made regarding luteal phase progestational support after normal folliular events. The overall importane of endometrial biopsy in the diagnosis of luteal adequay is supported by this study. The failure to detet an abnormality in the folliular phase does not protet against a delay in endometrial development. This study adds to our understanding of the pathophysiology of LPD. Defetive endometrial development has been attributed to aberrant folliulogenesis.4,9,10 While disruption of the developing follile may lead to an abnormal orpus luteum, this may not be the only soure of LPD. The seven ases of LPD doumented in this study had a delay in endometrial development of at least 3 days (mean = 3.6 ± 0.4 days, retrospetive dating; 4.1 ± 0.3 days, prospetive dating). Beause all seven ases have ompletely normal folliular phases LPD must have been aused by fators other than aberrant folliulogenesis. Defetive endometrial maturation ould have been beause of an end organ defiieny, a defet in orpus luteum transformation of a follile, or possibly an imperfet understanding of the entity oflpd. Defetive endometrium has been demonstrated in the presene of normal serum p.5-7 This observation suggests that abnormal steroid reeptor ativity may be the ause of the retarded development of the endometrium. Studies attempting to onfirm defetive steroid reeptor ativity have, hoever, demonstrated onfliting results.s Thus end organ defets as a ause of LPD has not been unequivoally demonstrated. Alternatively, DiZerega and Hodgen4 have suggested that insuffiient FSH ativity in the folliular phase may result in abnormal transformation of the developing follile into a orpus luteum. Subtle abnormalities may exist in gonadotropin seretion or pulsatility patterns that ere not studied in this investigation. Suh deviations ould have ad- 922 Grunfeld et al. LPD after rrmal folliulogenesis Fertility and Sterility

5 versely affeted the folliular apparatus and its eventual transition into the orpus luteum. In our study all patients, inluding those ith LPD, had normal folliular phase FSH values as ell as normal FSH surges. Although the folliular phase durations ere normal in all ases, they ere slightly longer hen LPD as diagnosed by prospetive dating. The observation of a slightly longer folliular phase may be a lue that subtle abnormalities may have existed in the dominant follile. An additional explanation is provided by M Neely and Soules ho has questioned the sensitivity and auray of the endometrial biopsy for the diagnosis of LPD.15 Inauray of the histologi dating may be an alternative explanation for the random ourrene of LPD in normal omen. Implantation is the only "gold standard" for endometrial adequay and endometrial sampling may overdiagnose LPD in ases here there is normal potential for pregnany to our. Previous studies that relied on retrospetive dating of the endometrium ere unable to diagnose LPD in oneption yles beause menses as unavailable as an endpoint. The ability for aurate prospetive dating of the endometrial biopsy may give us an opportunity to truly validate the importane of LPD. A prospetive study here endometrial biopsies are performed in arefully monitored pregnany yles should larify the signifiane of endometrial dating. REFERENCES 1. Davidson BJ, Thrasher TV, Seraj 1M: An analysis of endometrial biopsies performed for infertility. Fertil Steril 48: 770, Wentz AC: Diagnosing luteal phase inadequay. Fertil SteriI37:334, Davis OK, Berkeley AS, Naus GJ, Cholst IN, Freedman KS: The inidene of luteal phase defet in normal, fertile omen, determined by serial endometrial biopsies. Fertil Steril51:582, DiZerega GS, Hodgen GD: Luteal phase dysfuntion infertility: a sequel to aberrant folliulogenesis. Fertil Steril 35: 489, Gravanis A, Zorn J-R, Tanguy G, Nessmann C, Cedard L, Robel P: The "dysharmoni luteal phase" syndrome: endometrial progesterone reeptor and estradiol dehydrogenase. Fertil Steril 42:730, Belash J, Vanrell JA: Luteal phase defiieny: an inadequate endometrial response to normal hormone stimulation. Int J Fertil31:368, Spirtos NJ, Yureiz EC, Moghissi KS, Magyar DM, Sundareson AS, Bottoms SF: Pseudoorpus luteum insuffiieny: a study of ytosol progesterone reeptors in human endometrium. Obstet Gyneol 65:534, Jaobs MH, Belash J, Gonzalez-Merlo JM, Vanrell Ja, Wheeler C, Strauss JF, Blaso L, Wheeler JE, Lyttle CR: Endometrial ytosoli and nulear progesterone reeptors in the luteal phase defet. J Clin Endorinol Metab 64:472, Stouffer RI, Hodgen GD, Graves PE, Danfourth DR, Eyster KM, Ottobre JS: Charaterization of orpora lutea in monkeys after superovulation ith human menopausal gonadotropins or follile stimulating hormone. J Clin Endorinol Metab 62:833, Polan ML, Totora M, Caldell BV, DeCherney AH, Haseltine FP, Kase N: Abnormal ovarian yles as diagnosed by ultrasound and serum estradiol level. Fertil Steril 37:342, Landgren BM, Unden AL, Dizfalusy E: Hormonal profile ofthe yle in 68 normally menstruating omen. Ata Endorinol (Copenh) 94:89, Ryan KF: The endorine pattern and ontrol of the ovulatory yle. In Infertility Male and Female, Edited by V Insler, B Lunenfeld. Ne York, Churhill Livingstone, Publishers, 1986, p Noyes RW, Hertig AT, Rok J: Dating the endometrial biopsy. Fertil Steril1:3, Li T-C, Rogers AW, Lenton EA, Dokery P, Cooke I: A omparison beteen to methods of hronologial dating of human endometrial biopsies during the luteal phase, and their orrelation ith histologi dating. Fertil Steril48:928, MNeely MJ, Soules MR: The diagnosis ofluteal phase defiieny: a ritial revie. Fertil SteriI50:1, 1988 Grunfeld et al. LPD after normal fouiulogenesis 923