Uterine growth in the follicular phase of spontaneous ovulatory cycles and during luteinizing hormone-releasing hormone-induced cycles in women with normal or polycystic ovaries

Vol. 49, No.1, January 1988 Printed in U.S.A.

FERTILITY AND STERILITY Copyright 0 1988 The American Fertility Society

Uterine growth in the follicular phase of spontaneous ovulatory cycles and during luteinizing hormone-releasing hormone-induced cycles in women with normal or polycystic ovaries

Judith M. Adams, D.M.U.*t Seang L. Tan, M.D.:j:§ Michael J. Wheeler, Ph.D.11

David V. Morris, M.R.C.PJf Howard S. Jacobs, M.D.'\[ Stephen Franks, M.D.:j:

The Middlesex Hospital, St. Mary's Hospital Medical School, and St. Thomas's Hospital Medical School, London, England

The uterine response to follicular growth in luteinizing hormone-releasing hormone (LH-RH)-induced ovulatory cycles was assessed by serial ultrasound measurement of uterine cross-sectional area and endometrial thickness in 23 cycles in women with normal ovaries and 24 cycles in women with polycystic ovaries. Nine women with spontaneous ovulatory cycles also were studied. The authors correlated uterine cross-sectional area and endometrial thickness with follicle diameter (FD) and serum estradiol-17 (E 2 ). In women with either normal or polycystic ovaries, there was an E 2 -related increase in uterine cross-sectional area and endometrial thickness, but both uterine area and endometrial thickness were greater in the late follicular phase of women with polycystic ovaries compared with those with normal ovaries. Fertil Steril 49:52, 1988

Observations on cyclical changes in the uterus are derived primarily from histologic studies of the endometrium at various stages of the menstrual cycle. The most distinctive feature of the follicular phase is a progressive increase in the thickness of the endometrium produced by hyperplasia of both epithelial and stromal elements under the influ-

Received March 26, 1987; revised and accepted September 17, 1987. * Department of Ultrasound, The Middlesex Hospital. t Reprint requests: Ms. Judith M. Adams, Department ofUItrasound, The Middlesex Hospital, London WIN 8AA, England. :j: Department of Obstetrics and Gynaecology, St. Mary's Hospital Medical School. § Present address: Department of Obstetrics and Gynaecology, Kandang Kerbau Hospital, Singapore. II Department of Chemical Pathology, St. Thomas's Hospital. If Department of Endocrinology, The Middlesex Hospital.

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Uterine growth in the follicular phase

ence of ovarian secretion of estradiol. Estrogens stimulate both an increase in size of myometrial and endometrial cells, and an increase in their number. These effects involve a complex series of specific estrogen receptor-mediated events, including, of course, protein synthesis. 1 Pelvic ultrasonography is now used widely for assessment of follicular development in both spontaneous and induced menstrual cycles. 2 There have been reports of cyclical changes in the uterus during spontaneous cycles. 3 The endometrium has been assessed by sonography,4 and the appearances of normal and abnormal endometrium compared with histology.5 Correlation of the echo pattern of the endometrium with successful and unsuccessful ovulation induction and in vitro fertilization (IVF) programs also has been studied. 6 ,7 Our preliminary data have shown that ultrasound is useful in monitoring changes in uterine area in luteinizing hormone-releasing hormone (LH-RH)-induced cycles.8 Fertility and Sterility

In this more detailed study, we compare changes in uterine cross-sectional area and endometrial thickness with follicle diameter (FD) and serum estradiol-17 (E 2) in spontaneous menstrual cycles and in two groups of anovulatory women treated with pulsed LH -RH. MATERIALS AND METHODS

We studied nine cycles in nine women with a history of regular spontaneous menstrual cycles. We also studied 24 patients with anovulatory infertility in whom ovulation had been induced with pulsatile LH-RH therapy.9 Of these 24 patients, we analyzed 23 cycles in 14 women with hypogonadotrophic amenorrhoea (who had normal ovaries) and 24 cycles in 10 women with polycystic ovaries (peOs). Hypogonadotropic amenorrhea was diagnosed on the basis of normal or low gonadotrophin concentrations with evidence of estrogen deficiency (negative response to a progestin challenge and/or low E2)' These women had either normal ovaries or small ovaries with few or no follicles. peos were diagnosed primarily on ultrasound,lO,11 but all patients studied also had either a raised luteinizing hormone !follicle-stimulating hormone (LH/FSH) ratio (>3:1), raised serum testosterone (T), or both. A similar LH-RH dose regimen (15 ~g/90 minutes, usually given subcutaneously) was used for both groups of patients. In oligo menorrheic or amenorrheic women with peos, the endometrium was assessed by ultrasound prior to LH-RH therapy. Progestin withdrawal bleeding was induced if the endometrium was equal to or greater than 8 mm. In practice, however, none of the patients in the reported series required progestin treatment.

level of maximum depth of the uterus. Measurements included the echogenic interfaces between endometrium and myometrium and excluded the hypoechoic halo. 5 In spontaneous cycles, measurements were made daily from 5 days before ovulation and, in induced cycles, they were made on alternate days throughout the follicular phase, with more frequent observations, if necessary, around the predicted day of ovulation. Ovulation was defined retrospectively using both ultrasound and endocrine criteria, i.e., evidence of collapse of the dominant follicle with corpus luteum formation and serum progesterone (P) > 10 ng/ml in the subsequent midluteal phase. The days of the cycle were expressed in relation to the time of maximum follicular diameter in order to allow for betweenpatient comparisons. Serum E2 concentrations were measured during LH-RH-induced cycles in serial blood samples taken on the same day as the ultrasound scan. 9 RESULTS

Figure 1 shows the data from nine spontaneous cycles. The increase in diameter of the dominant follicle was accompanied by a progressive increase in both uterine cross-sectional area and endometrial thickness. There was a strong positive correlation of endometrial thickness with follicle diameter (r = 0.82, P < 0.001, n = 47). The growth rate of 24 22

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Pelvic Ultrasound All ultrasound measurements were performed by the same investigator using an Aloka sector scanner model SFD720 (Keymed Medical and Industrial Equipment Ltd., Southend-on-Sea, UK) with a 3.5-MHz long focused transducer. The maximum diameter of the dominant follicle was measured and only those cycles in which a single dominant follicle developed and ovulated were analyzed. Uterine cross-sectional area was calculated from the product of the maximum length (from fundus to cervix) and maximum depth (at the fundus) in the sagittal plane. lO The maximum thickness of the endometrium was measured at the Vol. 49, No.1, January 1988

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Figure 1 Changes in follicular diameter, uterine cross-sectional area, and endometrial thickness (Endo.) (mean ± SE) in nine normal women during the follicular phase of spontaneous ovulatory cycles.

Adams et al.

Uterine growth in the foUicular phase

53

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correlations also were observed when comparing E2 with either uterine cross-sectional area (r = 0.56, P < 0.02, n = 23) or endometrial thickness (r = 0.57, P < 0.01, n = 37).

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Figure 2 Changes in follicular diameter, serum estradiol concentrations (E 2 ), uterine area, and endometrial thickness (Endo.) (mean ± SE) in 16 ovulatory cycles of treatment of hypogonadotropic women (with normal ovaries) with LH-RH.

the dominant follicle in LH-RH-induced cycles in women with normal ovaries (Fig. 2) was similar to that in women with normal cycles and was related to a rise in serum E2 concentrations. As in spontaneous cycles, there was an associated increase in endometrial thickness, although the change in overall uterine area was not obvious until the late stages of the follicular phase. Similar correlations could be observed between follicular diameter, serum E2, uterine area, and endometrial thickness in women with PC Os in whom ovulation was induced with LH -RH. There were, however, differences in both uterine area and endometrial thickness among patients with normal ovaries and PCOs (Fig. 3). These differences were present throughout the follicular phase of the cycle, despite the fact that serum E2 levels and the follicular diameters in the two groups were identical. On day 0 ofLH-RH-induced ovulatory cycles, the mean (± standard deviation [SD]) uterine area in women with PC Os was 32.8 ± 8.4 cm2 compared with 25.3 ± 6.2 cm2 in women with normal ovaries (P < 0.001; Student's t-test). Endometrial thickness in the PCO group was 11.0 ± 1.2 mm compared with 9.0 ± 1.4 mm (P < 0.005) in the normal group. E2 concentrations were 464 ± 188 and 434 ± 169 pg/ml in the two groups; follicle diameters were 22.3 ± 2.4 and 21.0 ± 3.0 mm, respectively. A strong positive correlation was found between serum E2 and follicular diameter in LH-RH-induced cycles (r = 0.78, P < 0.01, n = 52). Positive 54

Adams et al.

Uterine growth in the follicular phase

We have shown that changes in both overall uterine area and endometrial thickness can be detected during the follicular phase of spontaneous and induced ovulatory cycles. Both the uterine area and endometrial thickness correlate with changes in serum E 2, associated with growth of the dominant follicle. The correlation of serum E2 concentrations with follicle diameter was observed in LH-RH-induced ovulatory cycles and this finding is in agreement with the results in spontaneous cycles. Ovarian scanning allows assessment of the response of the ovary to endogenous or exogenous gonadotropin stimulation while measurement of the uterine changes enables the investigator to monitor the functional capacity of the ovary. Thus, a progressive increase in uterine area and endometrial thickness in association with increasing follicular growth indicates that the follicle is secreting E2. Conversely, the development of an ovarian "follicle" without changes in the uterus suggests a nonfunctional cyst. Because there is a good deal of variation between individuals in both endometrial thickness and serum E 2, the absolute values are less important in establishing the response to induction of ovulation than are the progressive changes within each subject. 12

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Figure 3 Comparison of uterine area and endometrial thickness (mean ± SE) in the follicular phase of LH-RH-induced cycles in women who have normal ovaries (e) (n = 23) with results in women with polycystic ovaries (0) (n = 24). Mean values in nine women with spontaneous ovulatory cycles are shown by the open triangles (t:.). Fertility and Sterility

During LH-RH-induced cycles, there were differences in the response of the uterus between patients with normal ovaries and those with peos. Although follicular diameter and serum E2 concentrations were similar in the two groups, uterine area and endometrial thickness were greater in patients with peos. This may reflect a "background" of higher estrogen levels (particularly estrone) derived from peripheral conversion of androgen rather than from ovarian secretion. 12.13 The thickness of the endometrium in the follicular phase did not appear to affect the chance of conception either in women with normal ovaries or those with peos. There was no difference within each group in the mean endometrial thickness of conception versus nonconception cycles. The rate of early pregnancy loss following LH-RH-induced ovulation, however, was high in women with peos,14 suggesting that these differences in uterine morphology may be of clinical significance with regard to maintainance of early pregnancy. REFERENCES 1. Clark JH, Schrader WT, O'Malley BW: Mechanisms of steroid hormone action. In Textbook of Endocrinology (7th edition), Edited by JO Wilson, OW Foster. Philadelphia, WB Saunders 1985, p 55 2. 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 3. Piiroinen 0, Kaihola HL: Uterine size measured by ultrasound during the menstrual cycle. Acta Obstet Gynecol Scand 54:247,1975

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4. Fleischer A, Kalemeris G, Entman S: Sonographic depiction of the endometrium during normal cycles. Ultrasound Med BioI 12:271, 1986 5. Fleischer A, Kalemeris G, Machin J, Entman S, Everette JA: Sonographic depiction of normal and abnormal endometrium with histo-pathologic correlation. J Ultrasound Med 5:445, 1986 6. Brand T, Levy E, Grant T, Marut E, Leland J: Endometrial echo and its significance in female infertility. Radiology 157:225, 1985 7. Fleischer AC, Herbert CM, Sacks GA, Wentz AC, Entman SS, James AE Jr: Sonography of the endometrium during conception and non conception cycles of in vitro fertilization and embryo transfer. Fertil Steril 46:442, 1986 8. Adams J, Mason WP, Tucker M, Morris OV, Jacobs HS: Ultrasound assessment of changes in the ovary and the uterus during LHRH therapy. Ups J Med Sci 89:39, 1984 9. Mason P, Adams J, Morris OV, Tucker M, Price J, Voulgaris Z, Van der Spuy ZM, Sutherland I, Chambers GR, White S, Wheeler M, Jacobs HS: Induction of ovulation with pulsatile luteinising hormone releasing hormone. Br Med J 288:181, 1984 10. Parisi L, Tramonti M, Casciano S, Zurli A, Gazzarrini 0: The role of ultrasound in the study of polycystic ovarian disease. J Clin Ultrasound 10:167, 1982 11. Adams J, Polson OW, Franks S: Prevalence of polycystic ovaries in women with amenorrhoea and idiopathic hirsutism. Br Med J 293:355, 1986 12. Yen SSC: The polycystic ovary syndrome. Clin Endocrinol (OxO 12:177, 1980 13. Polson OW, Franks S, Reed MJ, Cheng RW, Adams J, James VHT: The distribution of estradiol in plasma in relation to uterine cross sectional area in women with polycystic or multifollicular ovaries. Clin Endocrinol (OxO 26:581, 1987 14. Adams J, Franks S, Polson OW, Mason HO, Abdulwahid N, Tucker M, Morris OV, Price J, Jacobs HS: Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotrophin releasing hormone. Lancet 2:1375, 1985

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Uterine growth in the follicular phase

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