Key words: polycystic ovary syndrome, hypothalmic-pituitary-ovarian axes

Transcription

1 Clin Pediatr Endocrinol 1999; 8(2), Copyright 1999 by The Japanese Society for Pediatric Endocrinology Clinical, Hormonal, and Radiological Studies at Baseline, During and After Long Term GnRH Analog (Leuprolide) Treatment in Adolescent Hirsute Females with Increased Ovarian Androgen Production Due to Polycystic Ovary Syndrome Ying Tai Chang, Mary Jean Suriano, Luigi Garibaldi, Linda Riddick, and Songya Pang Department of Pediatrics, Division of Endocrinology, University of Illinois, College of Medicine, Chicago, IL 60612, USA Abstract. To determine the site of primary pathogenesis in the hypothalamic-pituitary-ovarian (H-P-O) axes, which results in excess ovarian androgen secretion in polycystic ovary syndrome (PCOS), we investigated H-P-O axes function at baseline, during, and after long term H-P-O axes suppression in adolescent and young adult females with increased ovarian androgen production due to PCOS. Five hirsute females with menstrual disorders and PCOS, ranging from 12 to 22 yr of age, were evaluated for androstenedione ( 4-A) and testosterone (T) levels, LHRH-stimulated LH and FSH levels, pelvic ultrasound, bone density, and hirsute score before, during (at 3, 6, and 12 to 15 months) and after (1 to 4 months) 8 to 15 months of combined leuprolide acetate and oral contraceptive replacement therapies. Before treatment, baseline serum 4-A (8.6 ± 1.7 nm/l) and T levels (3.3 ± 1.7 nm/l) in the PCOS females were highly elevated (p<0.001) compared to levels in the normal females ( 4-A 4.7 ± 2.7 nm/l; T 1 ± 0.4 nm/l). LHRH-stimulated peak LH levels (85 ± 58 miu/ml) in the PCOS females were elevated but not significantly from the levels of normal females in the follicular phase of the menstrual cycle (60 ± 10 miu/ml). LHRH-stimulated FSH responses were similar between PCOS and normal females. The treatment with leuprolide acetate alone or with oral contraceptives in all patients resulted in suppression of elevated 4-A, T, and LHRH-stimulated LH and FSH levels beginning at 3 months to the end of treatment. Hirsute score and ovary size decreased during treatment. Following discontinuation of the treatment (1 to 4 months), serum T levels (2.4 ± 1.6 nm/l) in PCOS females rose promptly above the T levels of normal females. LHRH-stimulated LH levels (26 ± 21 miu/ml), however, were below the follicular phase response of normal females. Lumbar bone density did not change appreciably in any patient. Conclusion: The combined GnRH analog and oral contraceptive treatment effectively suppressed gonadotropin and ovarian androgen secretion in young females with PCOS, which resulted in improved hirsute score without causing osteoporotic changes. The prompt and excess rise in serum T levels in the face of only partially restored LHRH-stimulated LH secretion after discontinuation of the treatment indicates the presence of an intra-ovarian or systemic factor rather than a hypothalamicpituitary (gonadotropic) factor facilitating excess ovarian androgen secretion in PCOS. Key words: polycystic ovary syndrome, hypothalmic-pituitary-ovarian axes Received: March 1, 1999 Accepted: August 4, 1999 Correspondence: Dr. Ying Tai Chang, Department of Pediatrics (M/C 856), 840 S. Wood St., Chicago, IL 60612, USA

2 78 Chang et al. Vol.8 / No.2 Introduction The pathogenic mechanism of increased gonadotropin and ovarian androgen secretion in females with polycystic ovary syndrome (PCOS) is complex, and the primary etiological factor for altered hypothalamic-pituitary-ovarian (H-P-O) axes function in PCOS has not yet been defined (1-3). It has been postulated that the increased LH secretion stimulates excess ovarian androgen secretion resulting in increased peripheral estrogen formation, which contributes to further inappropriate gonadotropin secretion in women with PCOS (4-7). The short-term administration of a GnRH agonist reduced the serum gonadotropin and sex steroid concentrations in women with PCOS (8-15). Serum LH and androgen concentrations, however, returned to pre-treatment levels shortly after cessation of treatment (9, 11, 12, 15). We postulated that long-term suppression of gonadotropin and ovarian androgen secretion in PCOS females may result in the recovery of normal H-P-O axes function initially followed by a recurrent manifestation of PCOS. Evaluation of H-P-O axes function during the recovery and recurrent phases of PCOS may reveal the primary pathogenic site of an alteration in the H-P-O axes function. We therefore evaluated H-P-O axes function before, during, and after long-term combined GnRH analog and oral contraceptive replacement therapy in hyperandrogenic adolescents and young adult females with PCOS. In addition, the efficacy and safety of the combined GnRH analog and oral contraceptive were investigated by evaluating the clinical response, ovarian size, and bone density in the patients. Methods Patients Five adolescent and young adult females, ranging from 12 to 22 yr of age, who were evaluated at the University of Illinois Hospital for hirsutism and menstrual disorders enrolled in the study. Informed consents were obtained from all patients and legal guardians of minors according to the guidelines of the Institutional Review Board. All patients had manifestations of hyperandrogenism, including hirsutism and menstrual disorders (primary or secondary amenorrhea or menstrual irregularity). The pubertal, menstrual, and hirsute histories of the patients are shown in Table 1. Before initiation of GnRH analog treatment, all patients were evaluated to assess the severity of hirsutism using a modified Ferriman and Gallwey s hirsutism scoring system (1), and an ACTH stimulation test [basal and 60 min after IV 0.25 mg alpha 1-24 corticotropin (Cortrosyn)] ruled out adrenal cause of hirsutism in all subjects. LHRH stimulation test [gonadorelin hydrochloride (Factrel) 100 µg/m 2 IV, blood for LH and FSH levels at basal and min intervals for 3 hrs] was performed to assess gonadotropin secretion. A pelvic ultrasound for ovarian imaging and a bone densitometry study were obtained. The LHRH stimulation test was repeated at 3, 6, and 12 to 15 months of leuprolide acetate treatment with or without oral contraceptives, and 1 to 4 months after termination of leuprolide acetate and oral contraceptive treatments (Table 1). Basal serum testosterone (T) and androstenedione ( 4-A) were measured before, during (3, 6, 12 to 15 months), and after treatment (1 to 4 months). At 6 and 12 to 15 months of GnRH analog therapy, pelvic sonogram and vertebral double photon absorption bone densitometry were repeated. Patient 1 received 2 courses of treatment including the full course using daily leuprolide acetate for 12 months (#1), and a second course using leuprolide acetate depot for an additional 15 months (#1a), following a 4-month interval without any treatment. Patient # s 2, 3 and 5 were treated with leuprolide acetate depot (Lupron Depot) once a month. Patient 4 was treated with daily leuprolide acetate. Daily oral

3 H-P-O Axes Function in Young PCOS Females 79 Table 1 History of puberty, menstruation, and hirsutism, and course of leuprolide and oral contraceptive treatment in the PCOS patients Age at Age at Age Age Age of Menstrual disorder Hirsute/SM Leuprolide acetate Oral Patients start of onset of of of spontaneous before or after Rx score at treatment course contraceptive leuprolide hirsutism pubarche thelarche menarche onset of Rx Primary amenorrhea mg, qd 12 m Demulen 7 m-12 m 1a Primary amenorrhea 24 Depot 7.5 mg, qm 15 m Demulen 4 m-15 m Secondary 10 Depot 7.5 mg, qm 12 m Triphasil 4 m-12 m amenorrhea Irregular menese 14 Depot 7.5 mg, qm 12 m Demulen 4 m-12 m Irregular menses mg sc qd 4 m; Demulen 7 m-12 m 9.7 mg sc qd 5-8 m; 1.0 mg sc qd 9-12 m Irregular menses 23 Depot 7.5 mg, qm 8 m Triphasil 1 m-8 m mean (range) (12-22) ( ) (9-10.5) (9-11) (9-25) Patient #1 menstrual disorder was ascertained due to absence of spontaneous period between the two treatment courses and after final discontinuation of the second course of therapy. Patient #2 menstrual disorder was ascertained due to absence of spontaneous period after the discontinuation of the treatment. Patient #1 and 1a represent the first and second courses of the treatment. estrogen-progestin combination preparations [Demulen (ethynodiol diacetate/ethinyl estradiol) or Triphasil-28 (levonorgestrel/ethinyl estradiol)] were added to each patient s treatment 3 to 6 months after initiation of leuprolide acetate therapy, except patient 5 who was started on oral contraceptive pills from the first month of therapy. Patients were re-evaluated at 1 to 4 months after discontinuation of leuprolide acetate and oral contraceptive replacement treatments. Control females Normal basal levels of 4-A and T were obtained from 30 healthy females (13 to 40 yr of age) at all phases of the menstrual cycle (1, 16). The control LHRH-stimulated LH and FSH levels during the follicular phase of the menstrual cycle were obtained from 5 healthy females (13 to 26 yr of age) with normal menstrual history (16). Hormonal assay Serum 4-A and T levels were determined by radioimmunoassay (RIA) following celite chromatographic purification, and serum LH and FSH were determined by RIA as previously reported (16). The coefficients of variation between intra- and inter-assays were 10 to 15% for the 4-A and T assays and 15 to 20% for the LH and FSH assays (16). Statistics The statistical significance of the difference between pre-treatment versus treatment or posttreatment hormonal levels in the patients, and between the hormonal levels of the control normal females versus the patients was determined by a Wilcoxon signed rank test. Results Hormonal levels before, during and after leuprolide acetate treatment alone or combined leuprolide acetate and oral contraceptive treatment in the females with PCOS (Table 2) Before treatment with leuprolide acetate, the

4 80 Chang et al. Vol.8 / No.2 Table 2 Hormonal changes in five patients treated with leuprolide Treatment Basal level LHRH-stimulated level period 4A (nm/l) T (nm/l) LH (miu/ml) FSH (miu/ml) Pre-treatment 8.6 ± 1.7 a 3.3 ± 1.7 a 85 ± ± 3 3 months 2.8 ± 0.8 b 1.1 ± 0.8 b 6 ± 7 b 8 ± 3 6 months 3.8 ± 2.6 b 1.0 ± 0.4 b 7 ± 6 6 ± 6 12 months 3.1 ± 2.1 b 0.9 ± ± 5 b 6 ± 6 Post-treatment 4.8 ± ± 1.6 a,b 26 ± 21 a 21 ± 1 Normal females reference 4.7 ± ± ± ± 5 levels at follicular phase a p<0.01 or <0.02 against normal female levels. b p<0.01 or p<0.05 against pre-treatment levels. 4A: Androstenedione: to convert to ng/dl T: Tetstosterone: to convert to ng/dl baseline serum 4-A and T levels were significantly higher (p<0.01) in the 5 PCOS females compared to the normal females, and the LHRHstimulated peak LH levels were also elevated but not significantly from the response of normal females in the follicular phase of the menstrual cycle. The peak FSH response in the PCOS females, although high, was not statistically different from normal females. At evaluation of 3 months of leuprolide acetate treatment, LHRHstimulated peak LH and FSH responses were markedly suppressed, and serum 4-A and T levels were decreased compared to the pre-treatment levels of the patients and normal females. LHRH-stimulated peak LH and FSH levels, and serum 4-A and T levels remained suppressed at 6 and 12 to 15 months of the treatment course. One to 4 months after discontinuation of leuprolide acetate and oral contraceptive treatment, baseline serum 4-A levels in the patients rose to levels within the range of the normal females, while baseline serum T levels rose above the levels of the normal females. LHRH-stimulated peak LH levels, however, were significantly below the response of normal females in the follicular phase. LHRH-stimulated peak FSH levels were comparable to the response of normal females. Changes in hirsute score in the females with PCOS (Fig. 1) Hirsutism score decreased progressively in all patients, except one, after treatment initially with leuprolide acetate alone and then combined with oral contraceptives thereafter. In patient 1, rebound hirsute score was observed after discontinuation of the first course of treatment. Changes in bone density in the females with PCOS (Fig. 2) Patient 1 underwent a bone density study only during the first treatment course. At 6 months of leuprolide acetate treatment with additional oral contraceptives beginning at the 4th to 6th month of treatment, bone density of the lumbar spine of the 4 patients decreased slightly, but no further decrease in the bone density was noted at 12 to 15 months of the treatment course. The bone density of the femoral neck in the 3 patients examined showed no change during leuprolide acetate and oral contraceptive treatment (not shown on the figure). Changes in ovarian imaging determined by pelvic ultrasound (Table 3) Pelvic ultrasound before treatment in 3 patients demonstrated multiple cysts in one or both

5 H-P-O Axes Function in Young PCOS Females 81 Fig. 1 Hirsutism score before, during and after leuprolide acetate alone or combined with oral contraceptive treatment. Hirsutism score of each patient s pre-treatment, treatment, and post-treatment is depicted by the following symbols:. The number at the pre-treatment state corresponds to the patient # shown in Table 1. Patients 1 and 1a are the same patient receiving two treatment courses. indicates termination of treatment with leuprolide and oral contraceptive. Fig. 2 Lumbar bone density before and during leuprolide acetate therapy alone initially and combined with an oral contraceptive treatment in the females with PCOS. The number at the pre-treatment state correlates with the patient s # shown in Table 1. (%): Indicates the % of bone density compared to 20 yr old normal females. <90% are considered to be at risk for bone fracture. ( ): Indicates increased bone density compared to normal females. Table 3 Ovarian size (cm) on ultrasound before and during leuprolide acetate treatment Treatment month Patient # Ovary Pre-treatment Rt not visualized not visualized not visualized 1 Lt * * * Rt (multiple cysts) Lt (multiple cysts) (tiny cyst) Rt (multiple cysts) * Lt * Rt not visualized not visualized 4 Lt (cyst) * (cyst) Rt * * 5 Lt * * ovaries consistent with PCOS. In general, the size of the ovaries decreased slightly at 5 to 6 months and at 10 to 12 months of treatment. Adverse effects of leuprolide treatment One patient developed swelling in the lip which was resolved in 1 day, and another patient

6 82 Chang et al. Vol.8 / No.2 developed a skin rash a few days after the first dose of daily leuprolide acetate injection. The medication was discontinued for 5 days and reinitiated in each patient, and the side effects did not recur after resuming leuprolide acetate treatment. No other adverse reactions were observed. Discussion PCOS is manifested by hyperandrogenic symptoms, including hirsutism, and menstrual abnormality, such as oligomenorrhea, anovulation or amenorrhea, and infertility, with or without obesity. Increased ovarian production of androgens associated with inappropriately increased secretion of LH and defective follicular maturation is the characteristic features of PCOS (1, 2). Circulating T and LH levels are frequently elevated in PCOS females indicating the presence of altered H-P-O axes function. The pathophysiology and pathogenesis of the altered H-P-O axes in PCOS is complex and the primary etiological factor for the altered H-P-O axes is not yet defined (1-7, 17). The postulated theories on the pathogenesis of altered H-P-O axes in PCOS include: (i) a possible intrinsic factor(s) in the hypothalamic-pituitary axis which increases LH secretion, inducing ovarian thecal cell hyperplasia or ovarian cyst formation resulting in excessive secretion of androgens; or (ii) an intrinsic ovarian or non-cns systemic factor which induces thecal cell hyperplasia and cyst formation resulting in over production of androgens associated with the conversion of androgens to estrogen, which in turn stimulates excessive LH secretion from the pituitary; or (iii) excessive androgens from the adrenals or other sources which are converted to estrogen, thus stimulating increased LH secretion in PCOS (1-7, 17). It has been known that sustained high level stimulation with LHRH analogs down regulates gonadotropin secretion from the pituitary. Hence, suppression of gonadotropin and ovarian androgen secretion by LHRH analog treatment has been demonstrated in females with PCOS (8-15, 18, 19). Shaw et al. (15) treated 15 women with PCOS with a GnRH analog and observed a normalization of elevated gonadotropin levels and a suppression of serum E 2 and T, but the hormonal changes were not associated with consistent changes in ovarian volume or improvement in hirsute score (15). Calogera et al. reported a rebounding rise in serum LH, FSH, T, 4-A and E 2 levels 1 to 2 weeks after cessation of a 6-month GnRH analog treatment course, reaching the pre-treatment basal LH and T levels in 4 to 6 weeks (9). The study concluded that a positive correlation between the recovery of androgens and bio-lh supported the concept of LH-dependent hyperandrogenism (9). We postulated that suppression of gonadotropin and androgens over a longer period by combined GnRH analog and oral contraceptive treatment may provide a chance to restore the normal pituitary-ovarian axis function followed by a recurrent manifestation of altered H-P-O axes in PCOS patients. Thus, examination of the sequence of abnormalities in the H-P-O axes system during the recovery phase of PCOS may reveal the primary pathogenic site causing altered H-P- O axes function. Basal serum T and 4-A levels, and LHRHstimulated peak LH levels before leuprolide treatment in our PCOS patients were higher than levels in the normal females. During the longterm treatment course, T, 4-A and LHRH-stimulated peak LH and FSH levels were effectively suppressed. The findings of H-P-O axes function in our PCOS patients after longterm H-P-O axes suppression demonstrated the recurrent manifestation of prompt and excessive ovarian T secretion, while gonadotropin secretion was only partially recovered. These findings suggest that increased ovarian androgen secretion in PCOS females was facilitated by a primary ovarian or systemic factor rather than a hypothalamic-pituitary (gonadotropic) factor. It is likely that the primary factor facilitating increased

7 H-P-O Axes Function in Young PCOS Females 83 ovarian androgen secretion in those patients is related to hyperinsulinemia due to insulin resistance elucidated in the PCOS disorder (20, 21). However, ovaries of PCOS might have been primed by LH to overproduce androgens prior to suppression of gonadotropins by leuprolide, and a modest rise in LH secretion following a yearlong gonadotropin suppression may promptly have caused excess ovarian androgen production. Nevertheless, such priming effect of LH on PCOS, if it exists, does not contradict the assumption that an intra-ovarian or systemic factor(s) modulates gonadotropin effect in PCOS. It is also possible that a year-long suppression of H- P-O axes may not be sufficient to alter the vicious cycle in the H-P-O axes if the pathophysiology is caused by extra H-P-O axes factor or due to inadequate duration to nullify the pathophysiological cycle. A longer period of suppression of H-P-O axis may elucidate this query. Following cessation of leuprolide treatment, serum testosterone level rose promptly above normal while serum androstendione returned to normal female reference level. This suggests the presence of a factor facilitating conversion of androstenedione to testosterone in PCOS. Long-term GnRH agonist administration in pre-memopausal women reduced circulating estrogen and decreased bone density (13, 22, 23, 24). Bone density of the lumbar spine in our patients was initially decreased but not significantly from the normal control subject s bone density during the first 6 months of treatment with leuprolide acetate, as previously reported (13, 24). There was no further decrease in bone density after addition of oral contraceptives to our patients treatment course. This is consistent with the report that add-back estrogen prevents osteoporosis induced by LHRH analog therapy in PCOS (24, 25) and other disorders (13). GnRH analog treatment with or without oral contraceptives decreased hirsute score and hair diameter in both PCOS and idiopathic hirsute groups (26), as well as subjective improvement of hirsutism in women with PCOS (17). Overall, our patients hirsute scores showed similar efficacy of the combined leuprolide acetate and oral contraceptive treatment. In conclusion, this study demonstrated effective suppression of gonadotropin and ovarian androgen secretion, improvement of hirsutism, and prevention of osteoporosis by GnRH analog leuprolide acetate treatment combined with oral contraceptives. Following discontinuation of therapy, the prompt and excessive rebound of serum T levels in the presence of low LHRHstimulated peak LH levels compared to the patients pre-treatment levels and to the normal females levels suggests a primary ovarian or systemic factor other than a hypothalamic-pituitary (gonadotropic) factor facilitating excess ovarian androgen production in females with PCOS. Acknowledgments This study was supported by a grant from USPHS #R01 HD (SP). References 1. Pang S. Hirsutism. In: Lifshitz, editor, Pediatric endocrinology, 3rd ed. New York: Marcel Dekker, 1994: Bronson RA. Polycystic ovaries. In: Lifshitz, editor, Pediatric endocrinology, 2nd. ed. New York: Marcel Dekker 1990: Chrousos GP, Bringer J, Tolis G. Introduction: Intraovarian regulators and polycystic ovarian syndrome. Ann N Y Acad Sci 1983; 687: xiii. 4. Yen SS, Chaney C, Judd HL. Functional aberrations of the hypothalamic-pituitary system in polycystic ovarian syndrome: A consideration of the pathogenesis. In: James VHT, Serio M, Ginusti G, editors, The endocrine function of the human ovary. New York: Academic Press, 1976: Balen AH. Hypersecretion of luteinizing hormone and the polycystic ovary syndrome. Human Reprod 1993; 8 (suppl 2): Rebar RW, Judd HL, Yen SSC, Rakoff J, et al.

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