progesterone therapy*

Vol. 54, No.3, September 1990

FERTILITY AND STERILITY

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Copyright" 1990 The American Fertility Society

Serum concentrations of two endometrial proteins are not useful for monitoring postmenopausal estrogen/progesterone therapy*

Song-Guang Ren, M.D.t Glenn D. Braunstein, M.D.t* Marcelle Cedars, M.D.§

Joseph Gambone, D.O.§ Howard Judd, M.D.§

Cedars-Sinai Medical Center and University of California Los Angeles School of Medicine, Los Angeles, California

The human endometrium synthesizes and secretes several proteins including insulin-like growth factor-1-binding protein (lGFBP-1, placental protein 12 [PP12]) and PP14, a pregnancyassociated endometrial a2-globulin. These glycoproteins can be detected in luteal phase sera from cycling women and throughout pregnancy.1,2 The serum values of the endometrial proteins have a similar profile to that of progesterone (P), endometrial IGFBP-1 and serum P concentrations are correlated, and the serum levels of both endometrial proteins are significantly decreased in women with inadequate endometrium. 1-3 Therefore, it has been suggested that production of these proteins by the endometrium is P dependent. We undertook the present study to evaluate whether serum IGFBP-1 and PP14 measurements could be utilized to monitor the adequacy of progestogen dose in women receiving estrogens and progestogens for postmenopausal hormone replacement therapy. MATERIALS AND METHODS

Twenty-two postmenopausal women (median age 55, range 41 to 67 years) who had been postReceived January 16, 1990; revised and accepted May 3,1990.

* Supported in part by the Ciba-Geigy Corporation, Summit, New Jersey, and by grant RR 865 from the United States Public Health Service, Bethesda, Maryland. t Department of Medicine, Cedars-Sinai Medical Center and University of California Los Angeles School of Medicine. :\: Reprint requests: Glenn D. Braunstein, M.D., Department of Medicine, Room B118, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. § Department of Obstetrics and Gynecology, University of California Los Angeles School of Medicine.

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menopausal for an average of 5 years (range 1 to 14 years) without prior hormonal therapy were studied after obtaining informed consent. None of the 22 women had pathological changes other than atrophy noted on the pre hormone administration endometrial biopsy specimens. The women were divided into two groups: estradiol (E 2) group, n = 10, received 100 to 200 p,g of percutaneous E2 given for 28 days each month; E2 + medroxyprogesterone acetate (MPA) group, n = 12, received percutaneous E2 plus 10 mg of oral MPA given concurrently during the last 12 days of E2 administration. Endometrial biopsies were performed and serum samples collected during the last third of the final month ofthe 1st year oftherapy. This protocol was approved by the University of California Los Angeles Human Subjects Protection Committee. Concentrations of IGFBP-1 and PP14 in the sera were measured by homologous double antibody radioimmunoassays described in detail elsewhere. 4 The sensitivity of both assays was 7.8 p,g/L. The intra-assay variations were 6% at 20 p,g/L for IGFBP-1, and 8.8% at 120 p,g/L for PP14, and the interassay variations were <10%. Serum samples were stored frozen at -20°C for 1 to 3 years before analysis. Serum IGFBP-1 concentrations in frozen samples are stable for at least 1 year. Such data is not available for PP14. All samples from individual patients were run in the same assay. Student's paired t-test was used for statistical analysis. RESULTS

Before therapy, E2 and E2

+ MPA groups had 58

± 13 (mean ± SEM) and 35 ± 4 p,g/L of IGFBP-1 Fertility and Sterility

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those women whose biopsies had histologic changes consistent with a progestational effect, there were no significant differences in basal and post-therapy IGFBP-l concentrations. However, serum PP14 levels were slightly, but significantly higher (22 ± 1 ,."g/L versus 27 ± 1 ,."g/L, P = 0.018, SEM of differences between means = 2,."g/L).

E2

140 130 120 110 100

)

~

90

80 70 80

DISCUSSION

50 40 30 20 10 0

t:rt&i ~t

BEFORE AFTER

~ BEFORE

AFTER

Figure 1 Serum IGFBP-1 (top) and PP14 (bottom) levels in postmenopausal women before and after 1 year of treatment. Solid lines indicate mean levels. First column, E 2 , = women treated with percutaneous estradiol only; E2 + MPA = women treated with both percutaneous E2 and oral MP A.

in their respective sera. After 1 year of therapy, the serum concentrations ofIGFBP-l were 45 ± 6 and 33 ± 4 ,."g/L, respectively for the two groups. These values were not significantly different from the levels before treatment (SEM of difference between means = 11 and 3 ,."g/L, respectively, Fig. Before therapy, the serum PP14 concentrations were 25 ± 1 and 23 ± 1 ,."g/L for the E2 and E2 + MPA groups, respectively. After 1 year of therapy with E2 alone, serum PP14 levels decreased to 22 ± 1 ,."g/L (P = 0.02, SEM of differences between means = 1 ,."g/L). A small but significant (P = 0.04, SEM of difference between means = 2 ,."g/L) increase in PP14 concentrations to 27 ± 1 ,."g/L was found in the group treated with E2 + MP A, but there was considerable overlap between basal serum PP14 levels and thO!~e found after therapy (Fig. 1). After E2 therapy, all endometrial biopsy specimens demonstrated an estrogen effect. Eighty percent ofthe biopsies performed after E2 + MPA administration showed progestational effects, whereas the other 20% demonstrated only an estrogen effect. There were no significant differences between basal and post-therapy serum concentrations of IGFBP-l or PP14 in women whose endometrial biopsies showed an estrogen effect only. In

n

Vol. 54, No.3, September 1990

The present study demonstrates that postmenopausal women have detectable serum levels ofIGFBP-l and PPI4. Neither E2 nor E2 plus a progestogen given at the indicated doses increased serum levels of IGFBP-l, whereas E2 + MPA slightly increased PP14 concentrations. The serum levels of IGFBP-l after therapy were not correlated with the endometrial histology, whereas PP14 concentrations were slightly, but significantly increased in women whose endometrial histology had progestational changes. However, the overlap was great between basal and poSt-E2 + MPA therapy PP14 concentrations. Therefore, these data indicate that serum measurements of IGFBP-l and PP14 are not useful for monitoring postmenopausal hormonal replacement therapy with E2 and MPA. Previous in vitro studies have shown that P stimulates production and secretion of IGFBP-l and PP14 by nonpregnant endometrial tissue but failed to stimulate production of either of these proteins by tissue derived from pregnant women. 4 ,5 Wood and associates demonstrated the immunohistologic localization of PP14 in the endometrium of postmenopausal women after stimulation with an oral progestogen. s Therefore, endometrial concentrations of PP14 may be more reflective of the adequacy of progestogen-induced endometrial secretory transformation than serum levels. SUMMARY

Measurements of the serum concentrations of the endometrial proteins IGFBP-l and PP14 were made in an attempt to monitor the adequacy of the P effect in women receiving 1 year of 100 to 200 ,."g of percutaneous E2 for 28 days each month and 10 mg oral MPA given during the last 12 days of E2 administration. There were no significant changes in IGFBP-llevels;a small, but significant increase in PP14 levels after E2 plus MPA was noted, but there was substantial overlap between basal and postprogestogen therapy serum PP14 concentrations. Serum concentrations of PPI4, but not Ren et aI.

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IGFBP-l, were slightly higher in women whose endometrial biopsies demonstrated a P effect, but again, there was substantial overlap with the values found in women whose biopsies showed only an estrogen effect. Serum measurements of IGFBP-l and PP14 are not useful for monitoring postmenopausal replacement therapy with percutaneous E2 and oral MP A.

2.

3.

4.

Acknowledgments. We appreciate the excellent technical assistance of Ms. Judith Seliktar and the secretarial skills of Ms. Helene Zauderer. Hans Bohn, Ph.D., Behringwerk AG, Marburg, West Germany, kindly provided the reagents for measuring IGFBP-l and PPI4.

5.

6.

REFERENCES 1. Rutanen E-M, Koistinen R, Seppala M, Julkunen M, Suikkari A-M, Huhtala M-L: Progesterone-associated proteins

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PP12 and PP14 in the human endometrium. J Steroid Biochern 27:25, 1987 RutanenE-M, Koistinen R, Wahlstrom T, SjobergJ, Stenman U-H, Seppala M: Placental protein 12 (PPI2) in the human endometrium: tissue concentration in relation to histology and serum levels of PPI2, progesterone and oestradiol. Br J Obstet GynaecoI91:377, 1984 Joshi SG, Rao R, Henriques EE, Raikar RS, Gordon M: Luteal phase concentrations of a progestagen-associated endometrial protein (PEP) in the serum of cycling women with adequate or inadequate endometrium. J Clin Endocrinol Metab 63:1247,1986 Ren S-G, Braunstein GD: Progesterone and human chorionic gonadotropin do not stimulate placental proteins 12 and 14 or prolactin production by human decidual tissue in vitro. J Clin Endocrinol Metab 70:983, 1990 Bell SC, Hales MW, Patel S, Kirwan PH, Drife JO: Protein synthesis and secretion by the human endometrium and decidua during early pregnancy. Br J Obstet GynaecoI92:793, 1985 Wood PL, Waites GT, MacVicar J, Davidson AC, Walker RA, Bell SC: Immunohistological localization of pregnancy-associated endometrial a2-globulin (a2-PEG) in endometrial adenocarcinoma and effect of medroxyprogesterone acetate. Br J Obstet GynaecoI95:1292, 1988

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