- Email: [email protected]
Characteristics and incidence of dysfunctional ovulation patterns detected by ultrasound*
I
Vol. 47, No.4, April 1987 Printed in U.S.A.
FERTILITY AND STERILITY Copyright' 1987 The American Fertility Society
o
Characteristics and incidence of dysfunctional ovulation patterns detected by ultrasound * ,
!
Moustafa K. Eissa, M.D.t Robert S. Sawers, M.R.e.O.G.t:j: Melvyn F. Docker, M.sc.§ Se S. Lynch, Ph.D.11 John R. Newton, M.D.t University of Birmingham, Birmingham Maternity Hospital, and Central Birmingham Health Authority, Birmingham, England
The nature and incidence of normal and abnormal spontaneous ovarian cycles, identified with ultrasound and endocrine tracking, were examined in 45 regularly cycling infertile women with no definitive cause and 15 women who were apparently normal and were receiving donor insemination because of clearly infertile partners. In 136 cycles, four apparently distinct abnormal patterns were detected. The total incidence in the infertile group was 58% compared with 23% in the donor insemination group (P < 0.005). Twelve of 26 subjects who had at least three cycles tracked showed two different abnormalities, and 1 subject had three different abnormalities in five abnormal cycles. These results suggest that abnormal cycles are a significant factor in unexplained infertility and that diagnosis and treatment cannot be based on the study of a single cycle. Fertil Steril 47:603, 1987
In 1935, Stein and Leventhal 1 first postulated subcortical rupture of the ovarian follicles with entrapment of the oocyte. In 1967 Kase et aI. 2 suggested that luteinization without release of the oocyte might explain the descrepancy between the apparent ovulation rate and the pregnancy rate with clomiphene citrate therapy. Jewelewicz 3 coined the phrase "luteinized unruptured follicles 11 (LUFs). Received October 11, 1985; revised and accepted December 9, 1986. *Supported by grant GL417 from United Birmingham Hospitals Endowment Fund. tDepartment of Obstetrics and Gynaecology, University of Birmingham. :j:Reprint requests: Mr. Robert S. Sawers, Department of Obstetrics and Gynaecology, Birmingham Maternity Hospital, Edgbaston, Birmingham, B15 2TG, England. ~Department of Medical Physics and Biomedical Engineering, Birmingham Maternity Hospital. IIDepartment of Clinical Endocrinology, Central Birmingham Health Authority, United Kingdom. Vol. 47, No.4, April 1987
In 1978, Koninckx et aI. 4 and Marik and Hulka 5 independently described absence of the ovulation stigma at laparoscopy in infertile women with apparently normal ovulatory cycles. Koninckx et a1. 6 found that women without an ovulation ostium had relatively lower peritoneal fluid steroid concentrations during the early luteal phase than women with visible evidence of ovulation. The advent of high-resolution, real-time ultrasound scanning techniques has enabled the physical changes in the ovary during the menstrual cycle to be studied and correlated with the endocrine changes. 7 - 9 The normal pattern of follicular growth and its relationship to the hormone profile are now fairly well established,lO, 11 and a number of different abnormal patterns have been described. Failure of rupture of the follicle with signs of luteinization and continued growth to form a cystic structure in the luteal phase was observed by Coulam et aI.,12 Coutts et aI.,13 LiukEissa et a1. Ultrasound abnormal cycles
603
f konen eta!., 14 and Hamilton et a1. 15 Coutts et alP and Hamilton et al. 15 noted a poor progesterone (P) surge in association with this pattern. Kerin et a1. 16 recorded cycles with a slight decrease in follicular size and ultrasound signs of luteinization without evidence of follicular rupture 36 hours after the luteinizing hormone (LH) peak. In contrast to the previous studies, this pattern was associated with a normal hormone profile, including a good P surge. Both these patterns have been described as LUF. In addition to these, shrinkage of the follicle 24 hours before the LH peak has been describedY' 18 Despite a surge of interest in this field, however, considerable confusion remains over the exact nature of these abnormalities and their possible role in the etiology of infertility. After full investigation, the cause of infertility remains unexplained in a significant proportion of couples,. probably around 10%, although incidences of up to 24% have been reported. 19 - 21 Clearly, specialized centers will see a disproportionate number of such cases, and the figure will also depend on the range of investigations applied. Koninckx et al.,4 using Iaparoscopy, described late luteinization of unruptured follicles in 50% of cycles in apparently normal infertile women, whereas Liukkonen et al.,14 using ultrasound, described luteinization of un ruptured follicles in 57% of cycles. This incidence is much higher than that reported by Kerin et al. 16 of 13.6% in a mixed group of infertile patients, suggesting that these abnormalities may be a contributing factor in unexplained infertility. The current studies were designed first to clarify the nature of these abnormalities and second to assess their importance in infertility. MATERIALS AND METHODS
The subjects were 45 regularly cycling infertile women in whom no definitive cause had been identified (infertile group) and 15 apparently normal women who were receiving donor insemination because of clearly infertile partners (AID group). The first group of women were 23 to 40 years of age (median, 32 years), 33 had primary infertility of between 1.5 and 20 years (median, 5 years), and 12 had secondary infertility of between 2 and 10 years (median, 4 years); all but 2 had proven tubal patency. Thirty-nine had laparoscopy and the remainder had hysterosalpingography. Twenty-two subjects, all of whom had had 604
Eissa et al.
Ultrasound abnormal cycles
laparoscopy, showed no abnormality, 9 had minimal endometriosis (The American Fertility Society, Stage 1),22 and 1 had previously had a 6-cm endometriotic ovarian cyst that had resolved on treatment with danazol. Sixteen subjects including 3 of the endometriosis group had some evidence of tubal disease, 6 having had unilateral salpingectomy and 10 having had trivial adhesions. All their partners had at least three apparently satisfactory semen analyses. Twentytwo of those subjects therefore satisfied the criteria of Templeton and Penney21 for "normal infertile" women. The "normal infertile" and endometriosis groups did not differ significantly in age or type or duration of infertility from the total infertile group. The subjects in the AID group were from 23 to 40 years of age (median-, 31 years), 10 had primary infertility of between 2 and 15 years (median, 6 years), and 5 had secondary infertility of between 3 and 5 years (median, 4 years). All had proven tubal patency, 9 by laparoscopy and 6 by hysterosalpingography. Fourteen partners were azoospermic, and 1 had severe oligozoospermia. These subjects were therefore considered to form a relatively normal control group. All subjects had ultrasound and endocrine tracking from the midfollicular to midluteaI phase of one or more spontaneous cycles (range, 1 to 5; median, 2), and the total number of cycles studied in this way was 113. These data were used for the qualitative analysis of follicular growth and endocrine profiles. An additional 19 cycles in the infertile group and 4 cycles in the AID group were studied in sufficient detail for subsequent classification and were included in the quantitative analysis of the different patterns. Ultrasound observations were made from menstrual day 7, initially on alternate days until the mean follicular diameter (MFD) exceeded 13 mm and thereafter on a daily basis. Three realtime sector scanners were used (ATL MkIII, Advanced Technology Laboratories Inc., Bellevue, WA; IGE RT3000, General Electric Company, Milwaukee, WI; and Diasonics DFR 100, DiasonICs, Milpitas, CAl, with a 3- or 5-MHz transducer calibrated at 1540 m/second and employing the full-bladder technique of Hackeloer et a1. 8 The MFD was calculated from the maximum follicular diameter measured in three perpendicular planes as previously described. 23 Where changes suggestive ofluteinization were observed only the clearly definable cystic space was measured. SeFertility and Sterility
1 ,
(
,)
rum samples were obtained on the same occasions for radioimmunoassay of follicle-stimulating hormone (FSH), LH, estradiol (E2), and P. Analysis and graphic representation were performed with an expanded "BBC" model B microcomputer (Acorn Computers Ltd, Cambridge, England).l1 Incidences were compared by use of the chisquare test with Yates's correction. We have previously described detailed criteria of normal ovulation derived from conception cycles. l l The critical diagnostic criteria are the simultaneous occurrence of the LH peak and the maximum follicular diameter and the complete disappearance of the follicle or a decrease in the MFD of at least 60% within 24 hours thereafter.
RESULTS In 113 spontaneous cycles, 2 cycles with normal endocrine profiles had no follicles detected despite repeated scanning by different observers and presumed identification of the ovaries. One of these cycles resulted in conception. Fifty-one cycles appeared entirely normal, and conception occurred in 11 of those. There was no significant difference between any of the parameters in the conception and nonconception "normal" groups (Fig. 1A and B). The remaining 60 cycles, none of which resulted in conception, demonstrated one of four distinct abnormal patterns: 1. Apparently normal folliculogenesis with a normal endocrine profile but failure of follicular rupture and some decrease in the non-echogenic cystic space ("LUF" cycles). This pattern was recorded in 25 cycles (Fig. 2A and B). The only difference compared with the profiles of 11 spontaneous conception cycles was in the ultrasound observations from day + 1 relative to the LH peak. Follicular size decreased slightly with a mean drop on day + 1 of 12.9% (range, 5% to 23.8%), and the maximum reduction observed in any cycle on day + 2 was 37%. From day + 1 increased echodensity and irregularity of the follicular wall became obvious with apparent echogenic ingrowths into the cystic space (Fig. 3). The MFDs on day + 1 to day + 4 were significantly greater than for the spontaneous conception cycles (two-tailed Student's t-test; P < 0.001, 0.001, 0.05, and 0.02, respectively). 2. Normal follicular-phase growth but poor E2 surge, failure of rupture, continued growth subsequent to the LH peak, and deficient luteinization ("cyst" cycles). Vol. 47, No.4, April 1987
Sixteen cycles showing these characteristics were observed (Fig. 4A and B). The preovulatory E2 surge was significantly lower than in the spontaneous conception cycles (P < 0.001, day -3 to day 0). The follicles showed no or minimal signs of luteinization and continued to grow after the LH peak, forming a simple cyst, which persisted through the luteal phase. In six cases tracked into the next cycle, the cyst shrank and disappeared during menstruation. The P surge was approximately one-half of the normal values (P < 0.05, 0.001, 0.01, and 0.001 from day + 2 to day + 5, respectively). The gonadotropins appeared entirely normal. 3. Variable follicular-phase growth p2 terns and significant shrinkage 24 hours before the LH peak without clear evidence of rupture, associated with an apparently poor E2 surge and deficient gonadotropin surge, but essentially normal luteinization ("asynchronous" cycles). This pattern occurred in 12 spontaneous cycles (Fig 5A and B). The follicles showed a wide range in diameter when scanning was commenced in the midfollicular phase, several of these being larger than normal. The maximum diameter reached in the group was significantly smaller than normal (P < 0.001), and a significant decrease in size (mean, 33.5%; range, 9.1 % to 39.6%; paired t-test; P < 0.001) occurred 24 hours before the LH peak. The E2 peak was significantly lower than normal (P < 0.05), although its temporal relationship to the LH peak was normal. The maximum recorded LH and FSH values were significantly lower than normal (P < 0.01 and 0.05, respectively). The P profile did not appear significantly different from normal. 4. Anovulation despite regular menstruation ("no follicle" cycles). Seven cycles appeared to be associated with anovulation with no visible follicular growth and basal hormone levels. The incidence of the different types of abnormal cycles in the different groups is summarized in Table 1. The total incidence of abnormal cycles in the normal infertile group was 58% (29/50) compared with 23% (9139) of the AID group (X 2 = 9.5, P < 0.005). The incidence in the total infertile population was identical to that in the normal infertile subgroup, 58% (56/97 cycles), also highly significantly different from the AID controls (X 2 = 12.8, P < 0.001). The incidence of abnormal cycles in the 10 endometriosis patients was 42% (10/24 cyEissa et al.
Ultrasound abnormal cycles
605
fOLLICUU. III.TU
30 III
I • ClllCErtl. c··-.-
121 1I/L
LIIIIM! 21E1I
111
2t 15
l
~~M<~\~~
II
on' , 15 If 17 20 24 29 30 48 33 18 18 2D 14 11 , 14 10345'111811'533'332 ~
~
~
~
~
~ ~
~
• U d d
SEIVN ESTRIIDIOL
~
~ ~
Q
~
I ' COltE.TI8M
os .....•
31 IliL
la_1M ! 2SEII
1 • COICEPTIII
Q.--'-
u... !
HE.
21 1000
15
1. 500
-8 -1 -, -5 -4 -3 -2 -1
0 +1 +2 +3 +4 +5 ., +1 +1
1 =CIIIICEPTI•• 0-: --.La L86IIERlI ! 2S8I
SERUM 'RlSESTEl8ME
1IIII1IL 148
B
-I -1 -i -5 -4 -3 -2 -1 1 +1 +2 +3 ~ +5 ., +1 .. ItI'IS filii TIlE IIUlU 11 IEC. . .
120 100 II '0
.. "
A
"l/~r .
."
2t
",
+6 .,
~
cles), not significantly different from that in other groups. In the total infertility group the incidence of LUF, cyst, asynchronous, and "no-follicle" cycles was 20% (19/97), 22% (21197),8% (8/97), and 8% (8/97), respectively. The" relative incidence of these abnormalities within the total infertile group was 34%,38%,14%, and 14% of the abnormal cycles. In the normal infertile group dys606
Eissa et al. Ultrasound abnormal cycles
Figure 1 (A), Comparison of the MFD, E 2 , and P in 11 spontaneous conception cycles and 40 apparently normal spontaneous cycles in which conception did not occur (logmean ± 2 standard errors of the mean [SEM]). Day 0, day of maximum recorded LH. (B), Comparison of the FSH and LH profiles in 11 spontaneous conception cycles and 40 apparently normal spontaneous cycles in which conception did not occur (logmean ± 2 SEM). Day 0, day of maximum recorded LH.
functional cyst formation appeared to be relatively more common than the other abnormalities, 41% compared with 28% (LUF), 21% (asynchrony), and 10% (no follicle) of the abnormal cycles, although this difference is not significant. In the endometriosis group the LUF pattern predominated (6/10), compared with the cyst group (2/10), asynchrony group (2110), and no-follicle cycles (0/10). Fertility and Sterility
30
FOLLICULRR DlRIlETER
'"
• = CONCEPTION o = "LUF"
120
• = CONCEPTION o = "LUF"
lUlL
L0611ERN ! 2SE"
LOGIlERN ! 2SE"
25
100
20
80
15 10
40
n=
~
0' 3 8 09 57
~ 4
r P Jl' l' tI r 5
~ ~ ~ ~ ~ ~
0 "
20 515
l' lO
~ ~ "
015 3 8 311 2 9 "
SERUM ESTRRDIOL
2000 PMOltL
K
"
~
• = CONCEPTION
30
o = "LUF"
• • CONCEPTION o ="LUF" L0611ERN 12SE"
IUtL
25 1580 20
1000
15
10
500
SERUM PR06ESTERONE 140
NMOL/L
• = CONCEPTION o = "LUF"
B
~ 4
~ ~ ~ ~ ~ ~
0 " ~ " " " DRYS FRO" THE MRXIIII" LH RECORDED
K
Q ~
L0611EAN ! 2SE"
120 100 80 '0 40 20
....
A
o.IL
-I -7 ~ ~ ~ ~ ~ ~
0 " ~ " " " DRYS FRO" THE MRXIIII" LH RECORDED
K
Q ~
Forty-five subjects from both the AID and infertile groups were tracked for two or more spontaneous cycles. Twenty of those subjects were studied for three cycles and 14 subjects for four cycles. In 22 patients in whom the first cycle was normal, the same result was obtained in a second cycle in 11 (50%). Similarly in 23 patients in whom the first cycle was abnormal, the second cycle was also abnormal in 14 (61%). (i.e., overall, agreeVol. 47, No.4, April 1987
Figure 2 (A), Comparison of the MFD, E 2 , and P in 11 spontaneous conception cycles and 25 spontaneous LUF cycles (Jogmean ± 2 SEM). Day 0, day of maximum recorded LH. ***p < 0.001, **P < 0.002, *p < 0.05. (H), Comparison of the FSH and LH profiles in 11 spontaneous conception cycles and 25 spontaneous "LUF" cycles (Jogmean ± 2 SEM). Day 0, day of maximum recorded LH.
ment regarding "normality" or "abnormality" occurred between the first two cycles in only 55.5% without distinguishing the type of abnormality). Where two cycles had been either normal or abnormal and a third was studied, this agreed with the first two in 55%. Only 4 subjects who had three normal cycles and 2 patients with three abnormal cycles also had a fourth studied. In all cases, however, the fourth cycle agreed with the Eissa et al.
Ultrasound abnormal cycles
607
r DISCUSSION
Figure 3 Scan photograph of follicle showing signs of luteinization. Note thickened wall and filling in with echoes without actual rupture.
previous three cycles (Table 2). The overall rate of agreement of the third cycle with the first two was 55%. Where the first two were normal, 8 of 11 (73%) gave the same result compared with 4 of 11 (36%) in patients with two abnormal cycles. In 5 of the 13 subjects in whom the first two cycles gave a different result, the third cycle agreed with the first. Thus, overall, tracking a single cycle gave the same result as taking the "best of three" cycles in 73%. . Of the 26 patients who demonstrated abnormal cycles and who had at least three cycles tracked, 13 (50%) demonstrated a single abnormality, 12 (46%) showed two different abnormalities, and 1 subject had three different abnormalities in five abnormal cycles. Twenty-two infertile subjects and 7 in the AID group had sufficient cycles tracked to establish whether the predominant pattern was normal or abnormal on the basis of at least two of three cycles. The predominant pattern was abnormal in 15 of 22 infertile subjects compared with 1 of 7 in the AID group (X 2 = 4.24.; P < 0.05). Only 13 subjects in the "normal infertile" subgroup met these diagnostic criteria, and 9 of those showed a predominantly abnormal pattern. This was not significantly different from the AID gro:up. 608
Eissa et al.
Ultrasound abnormal cycles
The current and previous ultrasound studies of follicular growth in infertile women were prompted by the laparoscopic studies quoted previously,4, 5 which suggested that it was possible for a follicle to fail to rupture in an otherwise normal cycle. Laparoscopy alone is clearly able to provide physical observations on the ovary on a single occasion only. Conversely, ultrasound tracking, in association with the hormone profile, can provide a dynamic picture of ovarian behavior, and our own and previous work amply corroborate the finding offailure offollicular rupture in a significant proportion of infertile cycles. Whereas Koninckx and Brosens24 who used laparoscopy and Kerin et ai. 16 who used ultrasound to diagnose . failure of follicular rupture stated that such cycles were associated with normal luteinization, other authors 13 , 15 have found a poor P surge. The current study clearly shows that both situations exist. There are, however, two important differences between cycles with poor and "normal" luteinization. First those with a poor P surge have a relatively poor follicular-phase E2 surge. Second the follicular growth patterns are quite distinct during the luteal phase, those with a poor endocrine profile being associated with the formation of large follicular cysts in the luteal phase, with little ultrasound evidence of luteinization. There is little difficulty in distinguishing this pattern from normal, but where there is good ultrasound evidence of luteinization and some decrease in the size of the cystic space, it is essential to continue daily scanning for at least 2 days after the maximum MFD is reached to confirm that follicular rupture has not occurred. Careful examination of the reports of Coutts et aI.,t3 Kerin et aI.,16 and Liukkonen et aI. 14 suggests that their study groups included cycles of both types. Hamilton et aI. 15 described lutealphase cyst formation in association with apparently elevated follicular-phase E2 levels and elevated early luteal-phase P levels. Eleven of 27 such cycles in their study were stimulated, however, and cannot be compared with the spontaneous situation. Whether both patterns described in the current study should be termed L UF is a matter of semantics. Both patterns show luteinization without follicular rupture. We would submit, however, that the differences we have described justify different terminology. We suggest that the term LUF Fertility and Sterility
I =CONCEPTION =CYST FORMTIOI LOGIE•• ! 2SE.
FOLLICULRR DIIIETER
50 III
o
45
L20
I • CONCEPTION =CYST FORMITION LOGIER. 12SE.
lUlL
o
100
40
35 30
25
60
20
1
15 10
~
.to.......
lOt n= 5 0 2 7 3 I
rJ .~-~ -ts I
I
5
2000 1 P"OLtL
5
6 10
6
!.,~~
'4
'Q :+l. ?
'*' ~ t t--.
40
•
•• -t--I 7 12 10 16 13 15 13 10 11 6 6 6 7 10 8 11 , 5 3 3 3 3 2
SERUM ESTRRDIOL
20
= CONCEPnoN
...
~ = CYST
FORMlnoN LOGIERN ! 2SE"
I • CONCEPTION CYST FORMITION LOGIERN 12SE.
30 lUlL
o•
25 1500 20 1000
15
10
500
= CONCEPTION ~ = CYST FORMlnoN
SERUM PROGESTERONE 140 NMOLtL
B
~ ~ ~ ~ ~ ~ ~ ~ 0 d d ~ " ~ DRYS FRO. THE MlXIMU. LH RECORDED
N "
~
LOGIERN ! 2SE"
120
...
100
80
40 20
A
-8 -7 -6 -
-4 -3 -2 -1
0 +1 +2 +3 +4 +5 +, +7 +8
DRYS FRO. THE MlXIMUM LH RECORDED
should be reserved for cases showing a normal hormone profile, while the second group might be described by the term dysfunctional ovulation cyst. The general interest in LUF appears to have overshadowed other abnormalities of the cycle in which ultrasound is invaluable in making a diagnosis. The phenomenon of follicular shrinkage before the LH peak has been described before by Vol. 47, No.4, April 1987
Figure 4 (A), Comparison of the MFD, E 2 , and P in 11 spontaneous conception cycles and 16 spontaneous cyst-formation cycles (logmean ± 2 SEM). Day 0, day of maximum recorded LH. ***P < 0.001, **P < 0.01, *P < 0.05. (H), Comparison of the FSH and LH profiles in 11 spontaneous conception cycles and 16 spontaneous cyst-formation cycles (logmean ± 2 SEM). Day 0, day of maximum recorded LH.
Polan et alP and Geisthovel et al. 18 Anovulatory cycles are well recognized. 25 , 26 While groups II and IV may be identified with endocrine profiles, . group I may be identified only with the use of ultrasound, and for the diagnosis of type III both ultrasound and detection of the LH peak are essential. The role of these abnormalities in infertility will depend on their prevalence and must be deEissa et al.
Ultrasound abnormal cycles
609
I = CONCEPTION o = RSYNCHRONY
FOLLICULAR DIRIETER
III
30
LOSIERN
120
..
± 2SEM
25
I = CONCEPTION o = ASYNCHRONY LOGIERN ! 2SE"
SERUM LH
lUlL
100
••• ...
I
20
80
II 'I !
I]
15
1 10
I I
II
P'? 'I
Il,
I
60
I!h,~ Ht 1
40
u'm-Im 20
n=
o I
3
3 3
-8 -7 -6 2000
2
5 5 8 7 8 12 6 8 3 6 5 6 7 10 8 J1 9 5 3 3 -5 -4
PMOL/L
-3 -2 -1
o
6
3 2 2 3 3 2
~
t& Q~'~
tG
.~ to
-8 -7 -6 -5 -4 -3 -2
+1 +2 +3 +4 +5 +6 +7 +8
I =CONCEPTION o =RSYNCHRONY LOSKERN ± 2SEM
SERUM ESTRRDIOL
I
I
30
~ tij II~ II ~ ~
!!? I -I
o
+1 +2 +3 +4 +5 +6 +7 +8
I = CONCEPTION
lUlL
o
= RSYNCHRONY LOSIERN ± 2SEM
25
I
"
1500
~l
20
I' I
I
15
1000'
10 500
-8 -7 -6 -5 -4
-3 -2 -1
0 +1 +2 +3 +4 +5 +6 +7 +8
SERUM PROGESTERONE
I
o
=CONCEPTION
B
~ ~ ~ ~ ~ ~ ~ ~
0 "
"
n " "
DRYS FROM THE IIIXIIIIM LH RECORDED
M "
~
= RSYNCHRONY LOS KERN ! 2SEM
140 NItlL/L
120
I
100
~i! \! rII
80 60 40 20
A
~ ~ ~ ~ ~ ~ ~ ~
0 "
"
n " "
DRYS FRO" THE IIIXIIII" LH RECORDED
M "
~
termined by studies of normal and infertile groups. In the current study the incidence of abnormal cycles in the total infertile population (58%) was significantly higher than in the AID group (23%). This would suggest that these abnormalities may be a real cause of infertility. That the incidence was identical in the total infertile population and in the "normal infertile" subgroup can be explained by the fact that none 610
I
Eissa et al.
Ultrasound abnormal cycles
Figure 5 (A), Comparison of the MFD, E 2 , and P in 11 spontaneous conception cycles and 12 spontaneous asynchronous cycles (Jogmean ± 2 SEM). Day 0, day of maximum recorded LH. ***P < 0.001, *P < 0.05. (B), Comparison of the FSH and LH profiles in 11 spontaneous conception cycles and 12 spontaneous asynchronous cycles (logmean ± 2 SEM). Day 0, day of maximum recorded LH. **P < 0.01, *p < 0.05.
of the total infertile group had a definitive explanation for their infertility, although because of a variety of problems they could not all be classified as normal. The significance of abnormal cycles is supported by the fact that conception has not been observed in such cycles. 10, 11 We have demonstrated that an individual may show normal and several different types of abnormal cycles, and this degree of heterogeneity is in general Fertility and Sterility
Table 1. The Incidence of Different Abnormalities in 97 Spontaneous Cycles in 45 Infertile Women Compared with 39 Cycles in 15 Apparently Normal AID Subjects Patients
Group Total infertile Normal infertile Endometriosis AID ap bp
45 22 10 15
LUF
Cyst
Asynchronous
No follicle
'if
'if
'if
'if
20 16 25 10
22 24 8 8
8 12 8 5
8 6 0 0
Total 58% 58% 42% 23%
(56/97)a (29/50)b (10124) (9/39)
< 0.005. < 0.001.
agreement with the findings of Liukkonen et al. 14 and Kerin et al. 16 When two cycles were studied, a consistent result in terms of normality or abnormality was obtained in < 60%. In practice, therefore, it is necessary to study a third cycle in approximately 40% of subjects to obtain a consensus result. Even this may not necessarily give an accurate impression of the patient's cycles. In the current study the consensus result after three cycles was the same as that indicated by the first cycle in 73%, as regards "normal" or "abnormal" without distinguishing the type of abnormality. Where two consecutive cycles were normal the likelihood of a third being the same was double (73%) that when two consecutive cycles were abnormal (36%). The etiology of these abnormalities is unclear but is presumably related either to hypothalamicpituitary function or to abnormalities in the ovary itself. Studies designed to test both these hypotheses are in progress. The degree of variation observed within individuals suggests to us that the fault may lie within individual follicles. The problem of abnormal gametes is well recognized in male infertility and may exist also in female infertility. Trounson et a1. 27 reported failure of fertilization in oocytes obtained from patients with unexplained infertility, and Liukkonen et a1. 28 found that 37% of oocytes collected from patients showing LUF were morphologically abnormal with degenerative changes compared with 2.8% in patients having in vitro fertilization for other reasons. The fertilization rate was also Table 2. The Recurrence ofNormal or Abnormal Cycles in the Same Subjects, in 45 Women Studied for Two or More Spontaneous Cycles First cycle Normal Abnormal Total
No.
2nd agrees
3rd agrees
4th agrees
22 23 45
11122 (50%) 14/23 (61%)
8/11 (73%) 4/11 (36%) 12/22 (55%)
2/2 6/6
25/45 (56%)
Vol. 47, No.4, April 1987
4/4
reduced. Wardle et al.,29 however, reported no difference in fertilization rates with in vitro fertilization between "normal infertile" patients and those with tubal damage. A rational approach to correction of these abnormalities is difficult without a clear under" standing of the etiology. The inherent variability of spontaneous cycles means that it is illogical to attempt to tailor corrective therapy to suit the different abnormalities. In the first instance, however, empirical studies with existing therapeutic agents are required. Acknowledgments. We wish to thank Mr. Alex Bignell, M.Sc., and Mr. John Tighe, M.Sc., of the Department ofClini· cal Chemistry, Dudley Road Hospital, Birmingham, and Professor William P. Collins, D.Sc., of the Department ofObstetrics and Gynaecology, King's College Hospital, London, England, for their kind assistance with radioimmunoassays.
REFERENCES 1. Stein IF, Leventhal ML: Amenorrhoea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 29:181, 1935 2. Kase N, Mroueh A, Olson LE: Clomid therapy for anovulatory infertility. Am J Obstet Gynecol 98:1037,1967 3. Jewelewicz R: Management of infertility resulting from anovulation. Am J Obstet Gynecol 122:909, 1975 4. Koninckx PR, Heyns WJ, Corvelyn PA, Brosens IA: Delayed onset ofluteinization as a cause of infertility. Fertil Steril 29:266, 1978 5. Marik J, Hulka J: Luteinized unruptured follicle syndrome: a subtle cause of infertility. Fertil Steril 29:270, 1978 6. Koninckx PR, De Moor P, Brosens IA: Diagnosis of the luteinized unruptured follicle syndrome by steroid hormone assays on peritoneal fluid. Br J Obstet Gynaecol 87:929, 1980 7. Hackeloer BJ, Robinson HP: Ultraschalldarstellung des wachsenden Follikels und Corpus luteum in normalen physiologischen Zyklus. Geburtshilfe Frauenheilkd 38: 163, 1978 8. Hackeloer BJ, Fleming R, Robinson HP, Adam AH, Coutts JRT: Correlation of ultrasonic and endocrinologic assessment of human follicular development. Am J Obstet Gynecol 135:122, 1979
Eissa et al. Ultrasound abnormal cycles
611
9. Queenan JT, O'Brien GD, Bains LM, Simpson J, Collins WP, Campbell S: Ultrasound scanning of ovaries to detect ovulation in women. Fertil Steril 34:99, 1980 10. Zegers-Hochschild F, Lira CG, Parada M, Lorenzini EA: A comparative study of the follicular growth profile in conception and nonconception cycles. Fertil Steril 41:244, 1984 11. Eissa MK, Obhrai MS, Docker MF, Lynch SS, Sawers RS, Newton JR: Follicular growth and endocrine profiles in spontaneous and induced conception cycles. Fertil Steril 45:191, 1986 12. Coulam CB, Hill LM, Breckle R: Ultrasonic evidence for luteinization of unruptured preovulatory follicles. Fertil Steril 37:524, 1982 13. Coutts JRT, Adam AH, Fleming R: The deficient luteal phase may represent an anovulatory cycle. Clin Endocrinol 17:389, 1982 14. Liukkonen S, Koskimies AI, Tenhunen A, Ylostalo P: Diagnosis of luteinized un ruptured follicle (LUF) syndrome by ultrasound. Fertil Steril 41:26, 1984 15. Hamilton CJCM, Wetzels LCG, Evers JLH, Hoogland HJ, Muijtjens A, de Haan J: Follicle growth curves and hormonal patterns in patients with the luteinized unruptured follicle syndrome. Fertil Steril 43:541, 1985 16. Kerin JF, Kirby C, Morris D, McEvoy M, Ward B, Cox LW: Incidence of the luteinized unruptured follicle phenomenon in cycling women. Fertil Steril 40:620, 1983 17. Polan ML, Totora M, Caldwell BV, DeCherney AH, Haseltine FP, Kase N: Abnormal ovarian cycles as diagnosed by ultrasound and serum estradiol levels. Fertil Steril 37:342, 1982 18. Geisthovel F, Skubsch U, Zabel G, Schillinger H, Breckwoldt M: Ultrasonographic and hormonal studies in physiologic and insufficient menstrual cycles. Fertil Steril 39: 277, 1983 19. Jones GS, Pourmand K: An evaluation of etiologic factors and therapy in 555 private patients with primary infertility. Fertil Steril 13:398, 1962
612
Eissa et al.
Ultrasound abnormal cycles
20. Cox LW: Infertility: A comprehensive programme. Br J Obstet Gynaecol 82:2, 1975 21. Templeton AA, Penney GC: The incidence, characteristics and prognosis of patients whose infertility is unexplained. Fertil Steril 37:175,1982 22. The American Fertility Society: Revised American Fertility classification of endometriosis: 1985. Fertil Steril 43: 351, 1985 23. Eissa MK, Hudson K, Docker MF, Sawers RS, Newton JR: Ultrasound follicle diameter measurement: an assessment of interobserver and intraobserver variation. Fertil Steril 44:751, 1985 24. Koninckx PR, Brosens IA: The luteinized unruptured follicle syndrome. Obstet Gynecol Annu 11:175, 1982 25. Fraser IS, Michie EA, Wide L, Baird DT: Pituitary gonadotrophins and ovarian function in adolescent dysfunctional uterine bleeding. J Clin Endocrinol Metab 37: 407, 1973 26. Sherman BM, West JH, Korenman SG: The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentration during menstrual cycles of older women. J Clin Endocrinol Metab 42:629, 1976 27. Trounson AO, Leeton JF, Wood C, Webb J, Kovacs G: The investigation of idiopathic infertility by in vitro fertilization. Fertil Steril 34:431, 1980 28. Liukkonen S, Koskimies AI, Tenhunen A, Ylostalo P: In vitro fertilization; treatment of choice in luteinized unruptured follicle (LUF) syndrome. J In Vitro Fert Embryo Transfer 1:122, 1984 29. Wardle PG, Mitchell JD, McLaughlin EA, Ray BD, McDermott A, Hull MGR: Endometriosis and ovulatory disorder: reduced fertilisation in vitro compared with tubal and unexplained infertility. Lancet 2:236, 1985
Fertility and Sterility
Vol. 47, No.4, April 1987 Printed in U.S.A.
FERTILITY AND STERILITY Copyright' 1987 The American Fertility Society
o
Characteristics and incidence of dysfunctional ovulation patterns detected by ultrasound * ,
!
Moustafa K. Eissa, M.D.t Robert S. Sawers, M.R.e.O.G.t:j: Melvyn F. Docker, M.sc.§ Se S. Lynch, Ph.D.11 John R. Newton, M.D.t University of Birmingham, Birmingham Maternity Hospital, and Central Birmingham Health Authority, Birmingham, England
The nature and incidence of normal and abnormal spontaneous ovarian cycles, identified with ultrasound and endocrine tracking, were examined in 45 regularly cycling infertile women with no definitive cause and 15 women who were apparently normal and were receiving donor insemination because of clearly infertile partners. In 136 cycles, four apparently distinct abnormal patterns were detected. The total incidence in the infertile group was 58% compared with 23% in the donor insemination group (P < 0.005). Twelve of 26 subjects who had at least three cycles tracked showed two different abnormalities, and 1 subject had three different abnormalities in five abnormal cycles. These results suggest that abnormal cycles are a significant factor in unexplained infertility and that diagnosis and treatment cannot be based on the study of a single cycle. Fertil Steril 47:603, 1987
In 1935, Stein and Leventhal 1 first postulated subcortical rupture of the ovarian follicles with entrapment of the oocyte. In 1967 Kase et aI. 2 suggested that luteinization without release of the oocyte might explain the descrepancy between the apparent ovulation rate and the pregnancy rate with clomiphene citrate therapy. Jewelewicz 3 coined the phrase "luteinized unruptured follicles 11 (LUFs). Received October 11, 1985; revised and accepted December 9, 1986. *Supported by grant GL417 from United Birmingham Hospitals Endowment Fund. tDepartment of Obstetrics and Gynaecology, University of Birmingham. :j:Reprint requests: Mr. Robert S. Sawers, Department of Obstetrics and Gynaecology, Birmingham Maternity Hospital, Edgbaston, Birmingham, B15 2TG, England. ~Department of Medical Physics and Biomedical Engineering, Birmingham Maternity Hospital. IIDepartment of Clinical Endocrinology, Central Birmingham Health Authority, United Kingdom. Vol. 47, No.4, April 1987
In 1978, Koninckx et aI. 4 and Marik and Hulka 5 independently described absence of the ovulation stigma at laparoscopy in infertile women with apparently normal ovulatory cycles. Koninckx et a1. 6 found that women without an ovulation ostium had relatively lower peritoneal fluid steroid concentrations during the early luteal phase than women with visible evidence of ovulation. The advent of high-resolution, real-time ultrasound scanning techniques has enabled the physical changes in the ovary during the menstrual cycle to be studied and correlated with the endocrine changes. 7 - 9 The normal pattern of follicular growth and its relationship to the hormone profile are now fairly well established,lO, 11 and a number of different abnormal patterns have been described. Failure of rupture of the follicle with signs of luteinization and continued growth to form a cystic structure in the luteal phase was observed by Coulam et aI.,12 Coutts et aI.,13 LiukEissa et a1. Ultrasound abnormal cycles
603
f konen eta!., 14 and Hamilton et a1. 15 Coutts et alP and Hamilton et al. 15 noted a poor progesterone (P) surge in association with this pattern. Kerin et a1. 16 recorded cycles with a slight decrease in follicular size and ultrasound signs of luteinization without evidence of follicular rupture 36 hours after the luteinizing hormone (LH) peak. In contrast to the previous studies, this pattern was associated with a normal hormone profile, including a good P surge. Both these patterns have been described as LUF. In addition to these, shrinkage of the follicle 24 hours before the LH peak has been describedY' 18 Despite a surge of interest in this field, however, considerable confusion remains over the exact nature of these abnormalities and their possible role in the etiology of infertility. After full investigation, the cause of infertility remains unexplained in a significant proportion of couples,. probably around 10%, although incidences of up to 24% have been reported. 19 - 21 Clearly, specialized centers will see a disproportionate number of such cases, and the figure will also depend on the range of investigations applied. Koninckx et al.,4 using Iaparoscopy, described late luteinization of unruptured follicles in 50% of cycles in apparently normal infertile women, whereas Liukkonen et al.,14 using ultrasound, described luteinization of un ruptured follicles in 57% of cycles. This incidence is much higher than that reported by Kerin et al. 16 of 13.6% in a mixed group of infertile patients, suggesting that these abnormalities may be a contributing factor in unexplained infertility. The current studies were designed first to clarify the nature of these abnormalities and second to assess their importance in infertility. MATERIALS AND METHODS
The subjects were 45 regularly cycling infertile women in whom no definitive cause had been identified (infertile group) and 15 apparently normal women who were receiving donor insemination because of clearly infertile partners (AID group). The first group of women were 23 to 40 years of age (median, 32 years), 33 had primary infertility of between 1.5 and 20 years (median, 5 years), and 12 had secondary infertility of between 2 and 10 years (median, 4 years); all but 2 had proven tubal patency. Thirty-nine had laparoscopy and the remainder had hysterosalpingography. Twenty-two subjects, all of whom had had 604
Eissa et al.
Ultrasound abnormal cycles
laparoscopy, showed no abnormality, 9 had minimal endometriosis (The American Fertility Society, Stage 1),22 and 1 had previously had a 6-cm endometriotic ovarian cyst that had resolved on treatment with danazol. Sixteen subjects including 3 of the endometriosis group had some evidence of tubal disease, 6 having had unilateral salpingectomy and 10 having had trivial adhesions. All their partners had at least three apparently satisfactory semen analyses. Twentytwo of those subjects therefore satisfied the criteria of Templeton and Penney21 for "normal infertile" women. The "normal infertile" and endometriosis groups did not differ significantly in age or type or duration of infertility from the total infertile group. The subjects in the AID group were from 23 to 40 years of age (median-, 31 years), 10 had primary infertility of between 2 and 15 years (median, 6 years), and 5 had secondary infertility of between 3 and 5 years (median, 4 years). All had proven tubal patency, 9 by laparoscopy and 6 by hysterosalpingography. Fourteen partners were azoospermic, and 1 had severe oligozoospermia. These subjects were therefore considered to form a relatively normal control group. All subjects had ultrasound and endocrine tracking from the midfollicular to midluteaI phase of one or more spontaneous cycles (range, 1 to 5; median, 2), and the total number of cycles studied in this way was 113. These data were used for the qualitative analysis of follicular growth and endocrine profiles. An additional 19 cycles in the infertile group and 4 cycles in the AID group were studied in sufficient detail for subsequent classification and were included in the quantitative analysis of the different patterns. Ultrasound observations were made from menstrual day 7, initially on alternate days until the mean follicular diameter (MFD) exceeded 13 mm and thereafter on a daily basis. Three realtime sector scanners were used (ATL MkIII, Advanced Technology Laboratories Inc., Bellevue, WA; IGE RT3000, General Electric Company, Milwaukee, WI; and Diasonics DFR 100, DiasonICs, Milpitas, CAl, with a 3- or 5-MHz transducer calibrated at 1540 m/second and employing the full-bladder technique of Hackeloer et a1. 8 The MFD was calculated from the maximum follicular diameter measured in three perpendicular planes as previously described. 23 Where changes suggestive ofluteinization were observed only the clearly definable cystic space was measured. SeFertility and Sterility
1 ,
(
,)
rum samples were obtained on the same occasions for radioimmunoassay of follicle-stimulating hormone (FSH), LH, estradiol (E2), and P. Analysis and graphic representation were performed with an expanded "BBC" model B microcomputer (Acorn Computers Ltd, Cambridge, England).l1 Incidences were compared by use of the chisquare test with Yates's correction. We have previously described detailed criteria of normal ovulation derived from conception cycles. l l The critical diagnostic criteria are the simultaneous occurrence of the LH peak and the maximum follicular diameter and the complete disappearance of the follicle or a decrease in the MFD of at least 60% within 24 hours thereafter.
RESULTS In 113 spontaneous cycles, 2 cycles with normal endocrine profiles had no follicles detected despite repeated scanning by different observers and presumed identification of the ovaries. One of these cycles resulted in conception. Fifty-one cycles appeared entirely normal, and conception occurred in 11 of those. There was no significant difference between any of the parameters in the conception and nonconception "normal" groups (Fig. 1A and B). The remaining 60 cycles, none of which resulted in conception, demonstrated one of four distinct abnormal patterns: 1. Apparently normal folliculogenesis with a normal endocrine profile but failure of follicular rupture and some decrease in the non-echogenic cystic space ("LUF" cycles). This pattern was recorded in 25 cycles (Fig. 2A and B). The only difference compared with the profiles of 11 spontaneous conception cycles was in the ultrasound observations from day + 1 relative to the LH peak. Follicular size decreased slightly with a mean drop on day + 1 of 12.9% (range, 5% to 23.8%), and the maximum reduction observed in any cycle on day + 2 was 37%. From day + 1 increased echodensity and irregularity of the follicular wall became obvious with apparent echogenic ingrowths into the cystic space (Fig. 3). The MFDs on day + 1 to day + 4 were significantly greater than for the spontaneous conception cycles (two-tailed Student's t-test; P < 0.001, 0.001, 0.05, and 0.02, respectively). 2. Normal follicular-phase growth but poor E2 surge, failure of rupture, continued growth subsequent to the LH peak, and deficient luteinization ("cyst" cycles). Vol. 47, No.4, April 1987
Sixteen cycles showing these characteristics were observed (Fig. 4A and B). The preovulatory E2 surge was significantly lower than in the spontaneous conception cycles (P < 0.001, day -3 to day 0). The follicles showed no or minimal signs of luteinization and continued to grow after the LH peak, forming a simple cyst, which persisted through the luteal phase. In six cases tracked into the next cycle, the cyst shrank and disappeared during menstruation. The P surge was approximately one-half of the normal values (P < 0.05, 0.001, 0.01, and 0.001 from day + 2 to day + 5, respectively). The gonadotropins appeared entirely normal. 3. Variable follicular-phase growth p2 terns and significant shrinkage 24 hours before the LH peak without clear evidence of rupture, associated with an apparently poor E2 surge and deficient gonadotropin surge, but essentially normal luteinization ("asynchronous" cycles). This pattern occurred in 12 spontaneous cycles (Fig 5A and B). The follicles showed a wide range in diameter when scanning was commenced in the midfollicular phase, several of these being larger than normal. The maximum diameter reached in the group was significantly smaller than normal (P < 0.001), and a significant decrease in size (mean, 33.5%; range, 9.1 % to 39.6%; paired t-test; P < 0.001) occurred 24 hours before the LH peak. The E2 peak was significantly lower than normal (P < 0.05), although its temporal relationship to the LH peak was normal. The maximum recorded LH and FSH values were significantly lower than normal (P < 0.01 and 0.05, respectively). The P profile did not appear significantly different from normal. 4. Anovulation despite regular menstruation ("no follicle" cycles). Seven cycles appeared to be associated with anovulation with no visible follicular growth and basal hormone levels. The incidence of the different types of abnormal cycles in the different groups is summarized in Table 1. The total incidence of abnormal cycles in the normal infertile group was 58% (29/50) compared with 23% (9139) of the AID group (X 2 = 9.5, P < 0.005). The incidence in the total infertile population was identical to that in the normal infertile subgroup, 58% (56/97 cycles), also highly significantly different from the AID controls (X 2 = 12.8, P < 0.001). The incidence of abnormal cycles in the 10 endometriosis patients was 42% (10/24 cyEissa et al.
Ultrasound abnormal cycles
605
fOLLICUU. III.TU
30 III
I • ClllCErtl. c··-.-
121 1I/L
LIIIIM! 21E1I
111
2t 15
l
~~M<~\~~
II
on' , 15 If 17 20 24 29 30 48 33 18 18 2D 14 11 , 14 10345'111811'533'332 ~
~
~
~
~
~ ~
~
• U d d
SEIVN ESTRIIDIOL
~
~ ~
Q
~
I ' COltE.TI8M
os .....•
31 IliL
la_1M ! 2SEII
1 • COICEPTIII
Q.--'-
u... !
HE.
21 1000
15
1. 500
-8 -1 -, -5 -4 -3 -2 -1
0 +1 +2 +3 +4 +5 ., +1 +1
1 =CIIIICEPTI•• 0-: --.La L86IIERlI ! 2S8I
SERUM 'RlSESTEl8ME
1IIII1IL 148
B
-I -1 -i -5 -4 -3 -2 -1 1 +1 +2 +3 ~ +5 ., +1 .. ItI'IS filii TIlE IIUlU 11 IEC. . .
120 100 II '0
.. "
A
"l/~r .
."
2t
",
+6 .,
~
cles), not significantly different from that in other groups. In the total infertility group the incidence of LUF, cyst, asynchronous, and "no-follicle" cycles was 20% (19/97), 22% (21197),8% (8/97), and 8% (8/97), respectively. The" relative incidence of these abnormalities within the total infertile group was 34%,38%,14%, and 14% of the abnormal cycles. In the normal infertile group dys606
Eissa et al. Ultrasound abnormal cycles
Figure 1 (A), Comparison of the MFD, E 2 , and P in 11 spontaneous conception cycles and 40 apparently normal spontaneous cycles in which conception did not occur (logmean ± 2 standard errors of the mean [SEM]). Day 0, day of maximum recorded LH. (B), Comparison of the FSH and LH profiles in 11 spontaneous conception cycles and 40 apparently normal spontaneous cycles in which conception did not occur (logmean ± 2 SEM). Day 0, day of maximum recorded LH.
functional cyst formation appeared to be relatively more common than the other abnormalities, 41% compared with 28% (LUF), 21% (asynchrony), and 10% (no follicle) of the abnormal cycles, although this difference is not significant. In the endometriosis group the LUF pattern predominated (6/10), compared with the cyst group (2/10), asynchrony group (2110), and no-follicle cycles (0/10). Fertility and Sterility
30
FOLLICULRR DlRIlETER
'"
• = CONCEPTION o = "LUF"
120
• = CONCEPTION o = "LUF"
lUlL
L0611ERN ! 2SE"
LOGIlERN ! 2SE"
25
100
20
80
15 10
40
n=
~
0' 3 8 09 57
~ 4
r P Jl' l' tI r 5
~ ~ ~ ~ ~ ~
0 "
20 515
l' lO
~ ~ "
015 3 8 311 2 9 "
SERUM ESTRRDIOL
2000 PMOltL
K
"
~
• = CONCEPTION
30
o = "LUF"
• • CONCEPTION o ="LUF" L0611ERN 12SE"
IUtL
25 1580 20
1000
15
10
500
SERUM PR06ESTERONE 140
NMOL/L
• = CONCEPTION o = "LUF"
B
~ 4
~ ~ ~ ~ ~ ~
0 " ~ " " " DRYS FRO" THE MRXIIII" LH RECORDED
K
Q ~
L0611EAN ! 2SE"
120 100 80 '0 40 20
....
A
o.IL
-I -7 ~ ~ ~ ~ ~ ~
0 " ~ " " " DRYS FRO" THE MRXIIII" LH RECORDED
K
Q ~
Forty-five subjects from both the AID and infertile groups were tracked for two or more spontaneous cycles. Twenty of those subjects were studied for three cycles and 14 subjects for four cycles. In 22 patients in whom the first cycle was normal, the same result was obtained in a second cycle in 11 (50%). Similarly in 23 patients in whom the first cycle was abnormal, the second cycle was also abnormal in 14 (61%). (i.e., overall, agreeVol. 47, No.4, April 1987
Figure 2 (A), Comparison of the MFD, E 2 , and P in 11 spontaneous conception cycles and 25 spontaneous LUF cycles (Jogmean ± 2 SEM). Day 0, day of maximum recorded LH. ***p < 0.001, **P < 0.002, *p < 0.05. (H), Comparison of the FSH and LH profiles in 11 spontaneous conception cycles and 25 spontaneous "LUF" cycles (Jogmean ± 2 SEM). Day 0, day of maximum recorded LH.
ment regarding "normality" or "abnormality" occurred between the first two cycles in only 55.5% without distinguishing the type of abnormality). Where two cycles had been either normal or abnormal and a third was studied, this agreed with the first two in 55%. Only 4 subjects who had three normal cycles and 2 patients with three abnormal cycles also had a fourth studied. In all cases, however, the fourth cycle agreed with the Eissa et al.
Ultrasound abnormal cycles
607
r DISCUSSION
Figure 3 Scan photograph of follicle showing signs of luteinization. Note thickened wall and filling in with echoes without actual rupture.
previous three cycles (Table 2). The overall rate of agreement of the third cycle with the first two was 55%. Where the first two were normal, 8 of 11 (73%) gave the same result compared with 4 of 11 (36%) in patients with two abnormal cycles. In 5 of the 13 subjects in whom the first two cycles gave a different result, the third cycle agreed with the first. Thus, overall, tracking a single cycle gave the same result as taking the "best of three" cycles in 73%. . Of the 26 patients who demonstrated abnormal cycles and who had at least three cycles tracked, 13 (50%) demonstrated a single abnormality, 12 (46%) showed two different abnormalities, and 1 subject had three different abnormalities in five abnormal cycles. Twenty-two infertile subjects and 7 in the AID group had sufficient cycles tracked to establish whether the predominant pattern was normal or abnormal on the basis of at least two of three cycles. The predominant pattern was abnormal in 15 of 22 infertile subjects compared with 1 of 7 in the AID group (X 2 = 4.24.; P < 0.05). Only 13 subjects in the "normal infertile" subgroup met these diagnostic criteria, and 9 of those showed a predominantly abnormal pattern. This was not significantly different from the AID gro:up. 608
Eissa et al.
Ultrasound abnormal cycles
The current and previous ultrasound studies of follicular growth in infertile women were prompted by the laparoscopic studies quoted previously,4, 5 which suggested that it was possible for a follicle to fail to rupture in an otherwise normal cycle. Laparoscopy alone is clearly able to provide physical observations on the ovary on a single occasion only. Conversely, ultrasound tracking, in association with the hormone profile, can provide a dynamic picture of ovarian behavior, and our own and previous work amply corroborate the finding offailure offollicular rupture in a significant proportion of infertile cycles. Whereas Koninckx and Brosens24 who used laparoscopy and Kerin et ai. 16 who used ultrasound to diagnose . failure of follicular rupture stated that such cycles were associated with normal luteinization, other authors 13 , 15 have found a poor P surge. The current study clearly shows that both situations exist. There are, however, two important differences between cycles with poor and "normal" luteinization. First those with a poor P surge have a relatively poor follicular-phase E2 surge. Second the follicular growth patterns are quite distinct during the luteal phase, those with a poor endocrine profile being associated with the formation of large follicular cysts in the luteal phase, with little ultrasound evidence of luteinization. There is little difficulty in distinguishing this pattern from normal, but where there is good ultrasound evidence of luteinization and some decrease in the size of the cystic space, it is essential to continue daily scanning for at least 2 days after the maximum MFD is reached to confirm that follicular rupture has not occurred. Careful examination of the reports of Coutts et aI.,t3 Kerin et aI.,16 and Liukkonen et aI. 14 suggests that their study groups included cycles of both types. Hamilton et aI. 15 described lutealphase cyst formation in association with apparently elevated follicular-phase E2 levels and elevated early luteal-phase P levels. Eleven of 27 such cycles in their study were stimulated, however, and cannot be compared with the spontaneous situation. Whether both patterns described in the current study should be termed L UF is a matter of semantics. Both patterns show luteinization without follicular rupture. We would submit, however, that the differences we have described justify different terminology. We suggest that the term LUF Fertility and Sterility
I =CONCEPTION =CYST FORMTIOI LOGIE•• ! 2SE.
FOLLICULRR DIIIETER
50 III
o
45
L20
I • CONCEPTION =CYST FORMITION LOGIER. 12SE.
lUlL
o
100
40
35 30
25
60
20
1
15 10
~
.to.......
lOt n= 5 0 2 7 3 I
rJ .~-~ -ts I
I
5
2000 1 P"OLtL
5
6 10
6
!.,~~
'4
'Q :+l. ?
'*' ~ t t--.
40
•
•• -t--I 7 12 10 16 13 15 13 10 11 6 6 6 7 10 8 11 , 5 3 3 3 3 2
SERUM ESTRRDIOL
20
= CONCEPnoN
...
~ = CYST
FORMlnoN LOGIERN ! 2SE"
I • CONCEPTION CYST FORMITION LOGIERN 12SE.
30 lUlL
o•
25 1500 20 1000
15
10
500
= CONCEPTION ~ = CYST FORMlnoN
SERUM PROGESTERONE 140 NMOLtL
B
~ ~ ~ ~ ~ ~ ~ ~ 0 d d ~ " ~ DRYS FRO. THE MlXIMU. LH RECORDED
N "
~
LOGIERN ! 2SE"
120
...
100
80
40 20
A
-8 -7 -6 -
-4 -3 -2 -1
0 +1 +2 +3 +4 +5 +, +7 +8
DRYS FRO. THE MlXIMUM LH RECORDED
should be reserved for cases showing a normal hormone profile, while the second group might be described by the term dysfunctional ovulation cyst. The general interest in LUF appears to have overshadowed other abnormalities of the cycle in which ultrasound is invaluable in making a diagnosis. The phenomenon of follicular shrinkage before the LH peak has been described before by Vol. 47, No.4, April 1987
Figure 4 (A), Comparison of the MFD, E 2 , and P in 11 spontaneous conception cycles and 16 spontaneous cyst-formation cycles (logmean ± 2 SEM). Day 0, day of maximum recorded LH. ***P < 0.001, **P < 0.01, *P < 0.05. (H), Comparison of the FSH and LH profiles in 11 spontaneous conception cycles and 16 spontaneous cyst-formation cycles (logmean ± 2 SEM). Day 0, day of maximum recorded LH.
Polan et alP and Geisthovel et al. 18 Anovulatory cycles are well recognized. 25 , 26 While groups II and IV may be identified with endocrine profiles, . group I may be identified only with the use of ultrasound, and for the diagnosis of type III both ultrasound and detection of the LH peak are essential. The role of these abnormalities in infertility will depend on their prevalence and must be deEissa et al.
Ultrasound abnormal cycles
609
I = CONCEPTION o = RSYNCHRONY
FOLLICULAR DIRIETER
III
30
LOSIERN
120
..
± 2SEM
25
I = CONCEPTION o = ASYNCHRONY LOGIERN ! 2SE"
SERUM LH
lUlL
100
••• ...
I
20
80
II 'I !
I]
15
1 10
I I
II
P'? 'I
Il,
I
60
I!h,~ Ht 1
40
u'm-Im 20
n=
o I
3
3 3
-8 -7 -6 2000
2
5 5 8 7 8 12 6 8 3 6 5 6 7 10 8 J1 9 5 3 3 -5 -4
PMOL/L
-3 -2 -1
o
6
3 2 2 3 3 2
~
t& Q~'~
tG
.~ to
-8 -7 -6 -5 -4 -3 -2
+1 +2 +3 +4 +5 +6 +7 +8
I =CONCEPTION o =RSYNCHRONY LOSKERN ± 2SEM
SERUM ESTRRDIOL
I
I
30
~ tij II~ II ~ ~
!!? I -I
o
+1 +2 +3 +4 +5 +6 +7 +8
I = CONCEPTION
lUlL
o
= RSYNCHRONY LOSIERN ± 2SEM
25
I
"
1500
~l
20
I' I
I
15
1000'
10 500
-8 -7 -6 -5 -4
-3 -2 -1
0 +1 +2 +3 +4 +5 +6 +7 +8
SERUM PROGESTERONE
I
o
=CONCEPTION
B
~ ~ ~ ~ ~ ~ ~ ~
0 "
"
n " "
DRYS FROM THE IIIXIIIIM LH RECORDED
M "
~
= RSYNCHRONY LOS KERN ! 2SEM
140 NItlL/L
120
I
100
~i! \! rII
80 60 40 20
A
~ ~ ~ ~ ~ ~ ~ ~
0 "
"
n " "
DRYS FRO" THE IIIXIIII" LH RECORDED
M "
~
termined by studies of normal and infertile groups. In the current study the incidence of abnormal cycles in the total infertile population (58%) was significantly higher than in the AID group (23%). This would suggest that these abnormalities may be a real cause of infertility. That the incidence was identical in the total infertile population and in the "normal infertile" subgroup can be explained by the fact that none 610
I
Eissa et al.
Ultrasound abnormal cycles
Figure 5 (A), Comparison of the MFD, E 2 , and P in 11 spontaneous conception cycles and 12 spontaneous asynchronous cycles (Jogmean ± 2 SEM). Day 0, day of maximum recorded LH. ***P < 0.001, *P < 0.05. (B), Comparison of the FSH and LH profiles in 11 spontaneous conception cycles and 12 spontaneous asynchronous cycles (logmean ± 2 SEM). Day 0, day of maximum recorded LH. **P < 0.01, *p < 0.05.
of the total infertile group had a definitive explanation for their infertility, although because of a variety of problems they could not all be classified as normal. The significance of abnormal cycles is supported by the fact that conception has not been observed in such cycles. 10, 11 We have demonstrated that an individual may show normal and several different types of abnormal cycles, and this degree of heterogeneity is in general Fertility and Sterility
Table 1. The Incidence of Different Abnormalities in 97 Spontaneous Cycles in 45 Infertile Women Compared with 39 Cycles in 15 Apparently Normal AID Subjects Patients
Group Total infertile Normal infertile Endometriosis AID ap bp
45 22 10 15
LUF
Cyst
Asynchronous
No follicle
'if
'if
'if
'if
20 16 25 10
22 24 8 8
8 12 8 5
8 6 0 0
Total 58% 58% 42% 23%
(56/97)a (29/50)b (10124) (9/39)
< 0.005. < 0.001.
agreement with the findings of Liukkonen et al. 14 and Kerin et al. 16 When two cycles were studied, a consistent result in terms of normality or abnormality was obtained in < 60%. In practice, therefore, it is necessary to study a third cycle in approximately 40% of subjects to obtain a consensus result. Even this may not necessarily give an accurate impression of the patient's cycles. In the current study the consensus result after three cycles was the same as that indicated by the first cycle in 73%, as regards "normal" or "abnormal" without distinguishing the type of abnormality. Where two consecutive cycles were normal the likelihood of a third being the same was double (73%) that when two consecutive cycles were abnormal (36%). The etiology of these abnormalities is unclear but is presumably related either to hypothalamicpituitary function or to abnormalities in the ovary itself. Studies designed to test both these hypotheses are in progress. The degree of variation observed within individuals suggests to us that the fault may lie within individual follicles. The problem of abnormal gametes is well recognized in male infertility and may exist also in female infertility. Trounson et a1. 27 reported failure of fertilization in oocytes obtained from patients with unexplained infertility, and Liukkonen et a1. 28 found that 37% of oocytes collected from patients showing LUF were morphologically abnormal with degenerative changes compared with 2.8% in patients having in vitro fertilization for other reasons. The fertilization rate was also Table 2. The Recurrence ofNormal or Abnormal Cycles in the Same Subjects, in 45 Women Studied for Two or More Spontaneous Cycles First cycle Normal Abnormal Total
No.
2nd agrees
3rd agrees
4th agrees
22 23 45
11122 (50%) 14/23 (61%)
8/11 (73%) 4/11 (36%) 12/22 (55%)
2/2 6/6
25/45 (56%)
Vol. 47, No.4, April 1987
4/4
reduced. Wardle et al.,29 however, reported no difference in fertilization rates with in vitro fertilization between "normal infertile" patients and those with tubal damage. A rational approach to correction of these abnormalities is difficult without a clear under" standing of the etiology. The inherent variability of spontaneous cycles means that it is illogical to attempt to tailor corrective therapy to suit the different abnormalities. In the first instance, however, empirical studies with existing therapeutic agents are required. Acknowledgments. We wish to thank Mr. Alex Bignell, M.Sc., and Mr. John Tighe, M.Sc., of the Department ofClini· cal Chemistry, Dudley Road Hospital, Birmingham, and Professor William P. Collins, D.Sc., of the Department ofObstetrics and Gynaecology, King's College Hospital, London, England, for their kind assistance with radioimmunoassays.
REFERENCES 1. Stein IF, Leventhal ML: Amenorrhoea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 29:181, 1935 2. Kase N, Mroueh A, Olson LE: Clomid therapy for anovulatory infertility. Am J Obstet Gynecol 98:1037,1967 3. Jewelewicz R: Management of infertility resulting from anovulation. Am J Obstet Gynecol 122:909, 1975 4. Koninckx PR, Heyns WJ, Corvelyn PA, Brosens IA: Delayed onset ofluteinization as a cause of infertility. Fertil Steril 29:266, 1978 5. Marik J, Hulka J: Luteinized unruptured follicle syndrome: a subtle cause of infertility. Fertil Steril 29:270, 1978 6. Koninckx PR, De Moor P, Brosens IA: Diagnosis of the luteinized unruptured follicle syndrome by steroid hormone assays on peritoneal fluid. Br J Obstet Gynaecol 87:929, 1980 7. Hackeloer BJ, Robinson HP: Ultraschalldarstellung des wachsenden Follikels und Corpus luteum in normalen physiologischen Zyklus. Geburtshilfe Frauenheilkd 38: 163, 1978 8. Hackeloer BJ, Fleming R, Robinson HP, Adam AH, Coutts JRT: Correlation of ultrasonic and endocrinologic assessment of human follicular development. Am J Obstet Gynecol 135:122, 1979
Eissa et al. Ultrasound abnormal cycles
611
9. Queenan JT, O'Brien GD, Bains LM, Simpson J, Collins WP, Campbell S: Ultrasound scanning of ovaries to detect ovulation in women. Fertil Steril 34:99, 1980 10. Zegers-Hochschild F, Lira CG, Parada M, Lorenzini EA: A comparative study of the follicular growth profile in conception and nonconception cycles. Fertil Steril 41:244, 1984 11. Eissa MK, Obhrai MS, Docker MF, Lynch SS, Sawers RS, Newton JR: Follicular growth and endocrine profiles in spontaneous and induced conception cycles. Fertil Steril 45:191, 1986 12. Coulam CB, Hill LM, Breckle R: Ultrasonic evidence for luteinization of unruptured preovulatory follicles. Fertil Steril 37:524, 1982 13. Coutts JRT, Adam AH, Fleming R: The deficient luteal phase may represent an anovulatory cycle. Clin Endocrinol 17:389, 1982 14. Liukkonen S, Koskimies AI, Tenhunen A, Ylostalo P: Diagnosis of luteinized un ruptured follicle (LUF) syndrome by ultrasound. Fertil Steril 41:26, 1984 15. Hamilton CJCM, Wetzels LCG, Evers JLH, Hoogland HJ, Muijtjens A, de Haan J: Follicle growth curves and hormonal patterns in patients with the luteinized unruptured follicle syndrome. Fertil Steril 43:541, 1985 16. Kerin JF, Kirby C, Morris D, McEvoy M, Ward B, Cox LW: Incidence of the luteinized unruptured follicle phenomenon in cycling women. Fertil Steril 40:620, 1983 17. Polan ML, Totora M, Caldwell BV, DeCherney AH, Haseltine FP, Kase N: Abnormal ovarian cycles as diagnosed by ultrasound and serum estradiol levels. Fertil Steril 37:342, 1982 18. Geisthovel F, Skubsch U, Zabel G, Schillinger H, Breckwoldt M: Ultrasonographic and hormonal studies in physiologic and insufficient menstrual cycles. Fertil Steril 39: 277, 1983 19. Jones GS, Pourmand K: An evaluation of etiologic factors and therapy in 555 private patients with primary infertility. Fertil Steril 13:398, 1962
612
Eissa et al.
Ultrasound abnormal cycles
20. Cox LW: Infertility: A comprehensive programme. Br J Obstet Gynaecol 82:2, 1975 21. Templeton AA, Penney GC: The incidence, characteristics and prognosis of patients whose infertility is unexplained. Fertil Steril 37:175,1982 22. The American Fertility Society: Revised American Fertility classification of endometriosis: 1985. Fertil Steril 43: 351, 1985 23. Eissa MK, Hudson K, Docker MF, Sawers RS, Newton JR: Ultrasound follicle diameter measurement: an assessment of interobserver and intraobserver variation. Fertil Steril 44:751, 1985 24. Koninckx PR, Brosens IA: The luteinized unruptured follicle syndrome. Obstet Gynecol Annu 11:175, 1982 25. Fraser IS, Michie EA, Wide L, Baird DT: Pituitary gonadotrophins and ovarian function in adolescent dysfunctional uterine bleeding. J Clin Endocrinol Metab 37: 407, 1973 26. Sherman BM, West JH, Korenman SG: The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentration during menstrual cycles of older women. J Clin Endocrinol Metab 42:629, 1976 27. Trounson AO, Leeton JF, Wood C, Webb J, Kovacs G: The investigation of idiopathic infertility by in vitro fertilization. Fertil Steril 34:431, 1980 28. Liukkonen S, Koskimies AI, Tenhunen A, Ylostalo P: In vitro fertilization; treatment of choice in luteinized unruptured follicle (LUF) syndrome. J In Vitro Fert Embryo Transfer 1:122, 1984 29. Wardle PG, Mitchell JD, McLaughlin EA, Ray BD, McDermott A, Hull MGR: Endometriosis and ovulatory disorder: reduced fertilisation in vitro compared with tubal and unexplained infertility. Lancet 2:236, 1985
Fertility and Sterility