Changes of bioactive luteinizing hormone after laparoscopic ovarian cautery in patients with polycystic ovarian syndrome

Changes of bioactive luteinizing hormone after laparoscopic ovarian cautery in patients with polycystic ovarian syndrome

LE FERTILITY AND STERILITY Vol. 53, No.4, April 1990 Copyright e 1990 The American Fertility Society Printed on acid-free poper in U.S.A. Changes...

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Vol. 53, No.4, April 1990

Copyright e 1990 The American Fertility Society

Printed on acid-free poper in U.S.A.

Changes of bioactive luteinizing hormone after laparoscopic ovarian cautery in patients with polycystic ovarian syndrome

Masahiro Sakata, M.D.* Keiichi Tasaka, M.D., Ph.D. Hirohisa Kurachi, M.D., Ph.D.

Naoki Terakawa, M.D., Ph.D. Akira Miyake, M.D., Ph.D. Osamu Tanizawa, M.D., Ph.D.

Department of Obstetrics and Gynecology, Osaka University Medical School, Osaka, Japan

The serum levels ofbioactive luteinizing hormone (LH), immunoreactive LH, folliclestimulating hormone, androstenedione (A), and testosterone (T) were determined in nine anovulatory women with polycystic ovarian syndrome (PCOS) before and after laparoscopic ovarian cautery. Eight ovulated spontaneously and three conceived after treatment. Before treatment, the mean (±SEM) levels of bioactive LH, immunoreactive LH, A, and T were 51.4 ± 8.6 mIU/mL, 36.0 ± 4.5 mIU/mL, 1.98 ± 0.35 ng/mL, and 1.18 ± 0.13 ng/mL, respectively, which were significantly higher than those of five control women (19.2 ± 1.6 mIU/mL, 21.4 ± 1.2 mIU/mL, 0.54 ± 0.03 ng/mL, 0.28 ± 0.03 ng/mL). After treatment, the mean levels of these hormones had significantly decreased. Decreases in the levels of these hormones by laparoscopic ovarian cautery in women with PCOS may result in both restoration of the ovulatory cycle and achievement of pregnancy. Fertil SteriI53:610, 1990

Since Stein and Leventha11 first reported polycystic ovarian syndrome (peOS) in 1935, ovarian wedge resection has been thought to be effective for its treatment. However, the disadvantages of ovarian wedge resection are the invasive laparotomy and the possibility of intrapelvic adhesion. 2,3 Recently, the less invasive surgical procedure of laparoscopic ovarian cautery has been developed for treatment of anovulation in patients with peos. 4 After ovarian cautery, dramatic decreases in serum androgen levels have been demonstrated, 6 which are similar to those after ovarian wedge resection. 6 ,7 Women with peos have elevated serum levels of luteinizing hormone (LH) as well as elevated androgen levels. Their serum levels of bioactive LH Received August 1, 1989; revised and accepted December 20, 1989. * Reprint requests: Masahiro Sakata, M.D., Department of Obstetrics and Gynecology, Osaka University Medical School, I-I-50, Fukushima, Fukushimaku, Osaka 553, Japan.


Sakata et al.

Bioactive LH in ovarian cautery of peos

are also higher than those in regularly ovulatory women or chronically anovulatory women.8,9 To evaluate the hormonal effects of laparoscopic ovarian cautery, in this study we mainly investigated the changes of bioactive LH, immunoreactive LH, androstenedione (A), testosterone (T), and estradiol (E 2 ) before and after surgical treatment. MATERIALS AND METHODS

Patients Our criteria for peos were as follows: (1) chronic anovulation with amenorrhea or oligomenorrhea; (2) elevated serum LH levels and normal to low serum follicle-stimulating hormone (FSH) levels (LH/FSH ratios exceed 2.5); (3) elevated androgen (A and T) levels; and (4) laparoscopic or ultrasonographic 1o findings of enlarged ovaries with multiple cysts and thickened ovarian capsules. For laparoscopic ovarian cautery, we selected nine women who were consistent with a diagnosis of Fertility and Sterility

Table 1 Clinical Data on Patients with PCOS and Normal Regularly Cyclic Women as Controls· Controls Number Age (y) Duration of infertility (y) Height (cm) Weight (kg) Hirsutism Preoperative hormone levels Immunoreactive LH (mIU/mL) Bioactive LH (mIU/mL) FSH (mIU/mL) A (ng/mL) T (ng/mL) El (pg/mL) DHEAS (ng/mL)

5 34.2 ± 1.9

157.4 ± 2.2 46.6 ± 1.1


21.4 ± 19.2 ± 11.6 ± 0.54 ± 0.28 ± 120 ± 877 ±

1.2 1.6 1.4 0.03 0.03 16 61


29.1 ± 1.7 5.7 ± 1.5 155.7 ± 1.2 51.0 ± 3.1 3/9 (33.3%) 36.0 ± 4.5 b 51.4 ± 8.6 b 12.6 ± 1.2 1.98 ± 0.35 c 1.18 ± 0.13 c 196 ± 27 b 926 ± 156

• Data are means ± SEM. b P < 0.05 versus controls. c p < 0.01 versus controls.

PCOS and failed to respond to clomiphene citrate at a maximum dose of 150 mg/d. Their clinical characteristics are summarized in Table 1. They ranged from 20 to 38 years old with durations of infertility of 1.5 to 15 years. They were treated by laparoscopic electrocautery of the ovarian surface as described by Gjonnaess. 4 In brief, the ordinary three-puncture technique was used. The laparoscope was introduced through a subumbilical incision and grasping forceps were introduced through a lower abdominal incision. After the shapes ofthe ovaries were confirmed to be polycystic and tubal patency was assessed, unipolar biopsy forceps were held against the ovarian surface through a third puncture site. Several cautery points about 4 mm in diameter were made through the forceps. Blood samples were taken before the operation, daily for 1 week after the operation, and then once or twice a week until the first menses after the ovulation. The patients recorded basal body temperature (BBT). Ovulation was confirmed according to BBT, serum levels of progesterone (P), and also ultrasonographical findings. Five regularly cyclic subjects of 29 to 39 years old were selected as controls. They were confirmed to have cyclic ovulation with BBT and had no special gynecological findings. Their clinical data are also summarized in Table 1. Hormone Assays

The sera of blood samples were separated and frozen at -20°C for analyses of bioactive LH, immunoreactive LH, FSH, A, T, P, dehydroepianVol. 53, No.4, April 1990

drosterone sulfate (DHEAS), estrone (E 1), and E 2 • Serum bioactive LH was measured by assay of T production by dispersed rat Leydig cells in vitro as previously described. ll ,12 Leydig cells were prepared from adult rat testis by collagenase digestion and suspended in medium 199 containing 0.5% bovine serum albumin (BSA) and 0.1 mM 3-methylisobutyl xanthine. Aliquots of suspensions of 1 to 2 X 106 cells were incubated with various concentrations of standard hormone (lst IRP LH code No. 68/40) or sera in a final volume of 2 mL. After incubation for 3 hours under 95% air to 5% CO 2 with shaking at 150 cycles/min, the mixtures were centrifuged at 1,000 X g for 15 minutes, and aliquots of the supernatants were diluted with phosphate buffered saline/BSA for T assay. Bioactive LH in sera was measured by assay of T production in comparison with that of a standard preparation. The intra-assay and interassay coefficients of variation of bioactive LH were 8% and 14%, respectively. The serum concentrations of LH, FSH, E 2 , P, and T were measured in duplicate with commercial radioimmunoassay kits (LH, FSH: Daiichi Radioisotope, Tokyo, Japan; E 2 , P, T: Commissariat a L'Energie Atomique, Gif-sur-Yvette, France). The measurements of A, DHEAS, and El were performed by Teikokuzoki Pharmaceutical Company, Tokyo, Japan. Statistical Analysis

All values are expressed as mean ± SEM. Analysis of variance was used to analyze the data of women with PCOS. Statistical analysis between women with PC OS and control women was performed by Student's unpaired t-test. RESULTS

Of the nine patients with PCOS, eight ovulated spontaneously and the first menses occurred 26 to 56 days (42.9 ± 4.0 days) after the operation. Three conceived 10,14, and 50 weeks after the operation, respectively. The serum concentrations of bioactive LH, immunoreactive LH, and FSH before operation, in the 1st week after operation, and on the day of the early follicular phase after the first menses in the patients with PCOS are shown in Figure 1. Before operation, the mean ± SEM serum levels of bioactive LH was 51.4 ± 8.6 mIU/mL and that ofimmunoreactive LH was 36.0 ± 4.5 mIU /mL. Bioactive and immunoreactive LH both increased signifiSakata et al.

Bioactive LH in ovarian cautery of peDS


were 1.98 ± 0.35 ng/mL and 1.18 ± 0.13 ng/mL, respectively, which were significantly (P < 0.01) higher than those in normal women (0.54 ± 0.03 ng/mL, 0.28 ± 0.03 ng/mL). A rapid and significant (P < 0.01) decrease of A and T were observed after operation with a nadir of 0.78 ± 0.15 ng/mL on day 1 and 0.39 ± 0.08 ng/mL on day 2. There was no significant change in the serum E2 level after treatment (Fig. 1). Before operation, the mean ± SEM serum level of El in women with peos was 196 ± 28 pg/mL, which was significantly (P < 0.05) higher than that in normal women (120 ± 16 pg/mL). Slight decrease ofE l to 156 ± 17 pg/mL was observed on day 3 after operation and then a significant (P < 0.05) decrease to 133 ± 15 pg/mL occurred on the day of the early follicular phase after the first menses. There was no significant difference in the serum level of DHEAS between women with peos and normal women (Table 1).





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In the present study, of nine patients with peos who underwent ovarian cautery, eight ovulated

Figure 1 Changes in serum levels ofbioactive LH (e - - e), immunoreactive LH (0 - - - 0), immunoreactive FSH, androstenedione (A), testosterone (T), estradiol (E 2 ), and the bioactive LH/immunoreactive LH ratio after ovarian cautery in patients with PCOS. Points and bars are means ± SEM. EFP indicates the day of the early follicular phase after the first menses. *P < 0.05, ** P < 0.01 versus preoperative level.

cantly (P < 0.05) for the first 2 days after operation and then gradually fell. The serum levels of bioactive and immunoreactive LH were 25.8 ± 1.9 mIU / mL and 22.4 ± 2.2 mIU/mL, respectively, on the day of the early follicular phase after the menses, and these levels were significantly (P < 0.05) lower than those before the operation. The bioactive/immunoreactive LH ratio in patients with peos before operation was 1.43 ± 0.16, which was significantly (P < 0.05) higher than that of 0.90 ± 0.06 in control subjects. After treatment, the bioactive/ immunoreactive ratio ofLH decreased slightly, but not significantly, to 1.21 ± 0.16 (Fig. 2). The mean ± SEM serum FSH level increased significantly from 12.6 ± 1.2 mIU /mL before treatment to 17.2 ± 1.6 mIU/mL (P < 0.05) on day 1 and 19.0 ± 1.8 mIU/mL (P < 0.01) on day 2 after ovarian cautery, and then returned to 13.2 ± 0.4 mIU /mL on the day of the early follicular phase after the first menses. The mean ± SEM serum levels of A and T in peos women before operation 612

Sakata et al.

Bioactive LH in ovarian cautery af peDS

Figure 2 Comparison of bioactive LH and immunoreactive LH levels and bioactive/immunareactive ratios of women with ovulation (control) and patients with PCOS. Columns and bars represent means ± SEM. *P < 0.05; NS, not significant.

Fertility and Sterility

spontaneously and three became pregnant during the follow-up period. These findings confirmed previous reports that spontaneous ovulation occurred in 83% to 92% and pregnancy in 57% to 69% of the patients who were followed-up after this treatment4,5 or multiple punch biopsy.13 This procedure is more effective and less invasive than ovarian wedge resection. It also avoids the possibility of pelvic adhesion, which often occurs after ovarian wedge resection, and of ovarian hyperstimulation, which is associated with human menopausal gonadotropin-human chorionic gonadotropin therapy.5 The characteristically hormonal features of women with PCOS are elevated serum levels of LH and androgens. The serum levels of LH in patients with PCOS have been shown to be elevated by assays of both immunoactivity and bioactivity.8,g Treatment with gonadotropin-releasing hormone agonist or estrogen-progestogen is reported to reduce the level of bioactive LH in women with PCOS. 14,15 But this is the first report that laparoscopic ovarian cautery caused reductions of not only immunoreactive LH and androgens (A and T), but also ofbioactive LH after its temporary increase in women with PCOS. In patients with PCOS, ovarian cautery may result primarily in reduction of intraovarian androgens and then in decrease of the serum androgen levels. The decreased androgen level may cause the transient postoperative increases in LH by a negative feedback mechanism.5 The subsequent reduc~ tion in LH may be due to negative feedback by E2 with follicle maturation. The serum levels ofbioactive LH, immunoreactive LH, and FSH increased significantly on postoperative days 1 and 2, and then decreased, whereas the significantly reduced serum androgen levels persisted after the operation. All these hormonal changes except that of bioactive LH after ovarian cautery are consistent with those reported. 5,13,16,17 These changes are also similar to those observed after ovarian wedge resection.6,7 The temporal increase in FSH on postoperative days 1 and 2 may be caused by negative feedback due to decrease in the androgen levels or by reduction of intraovarian inhibin,18 resulting in follicle maturation and ovulation. Further investigations on endocrine effects after ovarian cautery are required to understand the etiology of PCOS.

Acknowledgments. We thank Ms. Sumi Tadokoro and Ms. Miyoko Matsumoto for excellent secretarial assistance, and Ms. Rieko Fujikawa for accurate technical assistance. Vol. 53, No.4, April 1990

REFERENCES 1. Stein IF, Leventhal ML: Amenorrhea associated with bilateral polycystic ovary. Am J Obstet Gynecol 29:181, 1935 2. Buttram VC, Jr, Vaquero C: Post-ovarian wedge resection adhesive disease. Fertil Steril26:874, 1975 3. Eddy CA, Asch RH, Balmaceda JP: Pelvic adhesions following microsurgical and macrosurgical wedge resection of the ovaries. Fertil Steril33:557, 1980 4. Gjonnaess H: Polycystic ovarian syndrome treated by ovarian electrocautery through the laparoscope. Fertil Steril41: 20,1984 5. Greenblatt E, Casper RF: Endocrine changes after laparoscopic ovarian cautery in polycystic ovarian syndrome. Am J Obstet Gynecol156:279, 1987 6. Judd HL, Rigg LA, Anderson DC, Yen SSC: The effects of ovarian wedge resection on circulating gonadotropin and ovarian steroid levels in patients with polycystic ovary syndrome. J Clin Endocrinol Metab 43:347,1976 7. Katz M, Carr PJ, Cohen BM, Millar RP: Hormonal effects of wedge resection of polycystic ovaries. Obstet Gyneco151: 437,1978 8. Lobo RA, Kletzky OA, Campeau JD, diZerega GS: Elevated bioactive luteinizing hormone in women with the polycystic ovary syndrome. Fertil Steril39:674, 1983 9. Lobo RA, Shoupe D, Chang SP, Campeau J: The control of bioactive luteinizing hormone secretion in women with polycystic ovary syndrome. Am J Obstet Gynecol 148:423, 1984 10. Yeh H-C, Weit WF, Thornton JC: Polycystic ovarian disease: US features in 104 patients. Radiology 163:111, 1987 11. Dufau ML, Mendelson CR, Catt KJ: A highly sensitive in vitro bioassay for luteinizing hormone and chorionic gonadotropin: testosterone production by dispersed Leydig cells. J Clin Endocrinol Metab 39:610, 1974 12. Tesone M, Ladenheim RG, Cheb-Terarrab R, Chiauzzi V, Solano A, Poderta E, Charreau EH: Comparison between bioactive and immunoreactive luteinizing hormone in ovariectomized streptozotocin induced diabetic rats: response to LH-releasing hormone. Endocrinology 119:2412, 1986 13. Sumioki H, Utsunomiya T, Matsuoka K, Korenaga M, Kadota T: The effect of laparoscopic multiple punch resection of the ovary on hypothalamo-pituitary axis in polycystic ovary syndrome. Fertil Steril 50:567, 1988 14. Meldrum DR, Tsao Z, Monroe SE, Braustein GD, Sladek J, Lu JKH, Vale W, Rivier J, Judd HL, ChangRJ: Stimulation of LH fragments with reduced bioactivity following GnRH agonist administration in women. J Clin Endocrinol Metab 58:755, 1984 15. Marrondis K, Evans A, Mamtora H, Anderson DC, Robertson WR: Bioactive LH in women with polycystic ovaries and the effect of gonadotrophin suppression. Clin Endocrinol (Oxf) 29:633, 1988 16. Aakvaag A, Gjonnaess H: Hormonal response to electrocautery of the ovary in patients with polycystic ovarian disease. Br J Obstet Gynaeco192:1258, 1985 17. Gjonnaess H, Norman N: Endocrine effects of ovarian electrocautery in patients with polycystic ovarian disease. Br J Obstet Gynaecol 94:779, 1987 18. Tanabe K, Gagliano P, Channing CP, Nakamura Y, Yoshimura T, lizuka R, Fortuny A, Sulewski J, Rezai N: Levels of inhibin-F activity and steroids in human follicular fluid from normal women and women with polycystic ovarian disease. J Clin Endocrinol Metab 57:24, 1983

Sakata et aI. Bioactive LH in ovarian cautery of peDS