Naltrexone treatment restores menstrual cycles in patients with weight loss-related amenorrhea*

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1 FERTILITY AND STERILITY Copyright American Society for Reproductive Medicine Vol. 64, No.5, November 1995 Printed on acid free paper in U. S. A Naltrexone treatment restores menstrual cycles in patients ith eight loss-related amenorrhea* Alessandro D. Genazzani, M.D.t:j: Felice Petraglia, M.D.t Mario Gastaldi, M.D.t Cristina Volpogni, M.D.t Ombretta Gamba, M.D. t Andrea R. Genazzani, M.D. University of Modena, Modena, and University of Pisa, Pisa, Italy Objective: To evaluate hether the efficacy of naltrexone administration in patients ith hypothalamic amenorrhea correlates to the response to an acute naloxone test. Design: Thirty patients ith hypothalamic amenorrhea associated ith eight loss ere studied. After naloxone test (4 mg in bolus IV) patients ere divided in to groups: group A, nonresponsive (n = 15) and group B, responsive (n = 15). Group A underent to cycles of hormonal replacement therapy ith E2 patches and medroxyprogesterone acetate. Then all patients ere administered naltrexone at the dosage 50 mg/d orally for 6 months. A third group of 10 amenorrheic patients ere treated ith oral placebo ith the same schedule. Results: Plasma gonadal steroid levels increased in all patients and in 24 of 30 patients the menstrual bleeding occurred ithin 90 days from the beginning of treatment. After 6 months from naltrexone discontinuation, 18 of 24 patients still shoed the occurrence of menstrual cycles. Luteinizing hormone plasma levels and LH pulse amplitude increased after 3 months of treatment and remained unchanged 6 months after naltrexone suspension. Plasma FSH levels did not sho any change in any patient. The body mass index increased after 3 months in all patients ho menstruated. Patients treated ith placebo did not sho any significant change in gonadotropins and gonadal steroid plasma levels. Conclusions: The present study supports the efficacy ofnaltrexone therapy for patients ith hypothalamic amenorrhea either responsive or nonresponsive to naloxone test. Fertil Steril 1995;64:951-6 Key Words: Hypothalamic amenorrhea, eight loss, luteinizing hormone, opioids, naltrexone Hypothalamic amenorrhea associated ith eight loss is a model of hypogonadism characterized by neuroendocrine aberrations, hich affects the neuroendocrine hypothalamic activity (1) as ell as the release of several hypophyseal hormones (2-6). Amenorrheic patients have altered LH (3), GH (5), and PRL (2, 6) secretory patterns. A disregulation of some central neuromodulators has been suggested. In particular, an altered activity of opioidergic system has been proposed, because an acute in- Received June 22, 1994; revised and accepted May 30, * Supported in part by the CNR (National Research Council, Rome, Italy) program "Altri Interventi" AI (A.D.G.). t Department of Obstetrics and Gynecology, University of Modena. :j: Reprint requests: Alessandro D. Genazzani, M.D., Department of Obstetrics and Gynecology, University of Modena, Via del Pozzo 71, Modena, Italy (FAX: ). Department of Obstetrics and Gynecology, University of Pisa. jection of naloxone, an opioid receptor blocker, increases LH pulse frequency and amplitude in healthy omen but not in amenorrheic patients (7, 8). Hoever, hen naltrexone, a long-acting specific blocker of opioidergic receptors, as used to restore menstrual cyclicity in patients ith hypothalamic amenorrhea, conflicting results have been reported. Remorgida et al. (9) shoed no difference beteen placebo and naltrexone, hereas Armeanu et al. (l0, 11) reported a moderate effect of naltrexone on LH episodic release in patients ith eight loss related amenorrhea (10, 11) but not in anorexia nervosa (10). Conversely, Wildt and Leyendecker (12) and Wildt et al. (13) reported the restoration of normal cyclicity in hypothalamic amenorrhea using naltrexone at the standard dose of 50 mg/d (12) or higher (13). Moreover, it is knon that gonadal steroids modulate the response oflh to naloxone injection in hypo- Vol. 64, No.5, November 1995 Genazzani et al. Naltrexone administration in hypothalamic amenorrhea 951

2 estrogenic omen (14) and in normal men (15), demonstrating an interaction beteen gonadal steroids and opioids in affecting gonadotropin release. On the basis ofthese data, the present study aimed to evaluate the responsiveness oflh to acute naloxone infusion in patients ith hypothalamic amenorrhea treated ith naltrexone and its efficacy in restoring menstrual cyclicity. Subjects MATERIALS AND METHODS Among all patients ith menstrual cycle disturbances coming to our department, 40 patients affected by hypothalamic amenorrhea and reduced body mass index (BM!) ere enrolled for this study. All subjects gave informed consent and the study protocol as approved by the Human Investigation Committee of the University of Modena. Criteria for inclusion ere [1] absence of menstrual cycles for ~6 months before study; [2] normal plasma levels of adrenal cortex, thyroid hormones, PRL, and androgens; [3] history of eight loss in the last 18 months; [4] body eight loer than the ideal body eight and BMI < 20 and no eight gain during the 6 eeks preceding the study; [5] absence of depression or psychiatric diseases assessed according to Diagnostic and Statistical Manual-III (Revised) criteria (16); and [6] no intense training for agonistic purposes. A naloxone (Narcan; Crinos, Milan, Italy) test for LH determination (4 mg in bolus at time 0 and blood sampling at times -75, -60, -45, -30, -15, 0, 15, 30, 45, 60, 75, and 90 minutes) as performed in all 40 patients. The naloxone test as considered positive hen LH plasma levels increased at least tofold from the value observed at time 0, ithin 60 minutes from the administration. On the basis of the response to the naloxone test, amenorrheic patients ere divided in to groups: group A, (n = 15) those ho did not respond and group B, (n = 15) those ho responded to the test. Patients of group A underent to cycles of hormonal replacement therapy (HRT) (24 days each, ith a 7 -day interval) ith the folloing schedule: E2 patch (100 Mg, Estroclim; SigmaTau, Pomezia, Italy), replaced tice a eek, for 24 days (days 1 to 24) and medroxyprogesterone acetate (Farlutal; Farmitalia, Milan, Italy) at the dose of 10 mg/d from days 12 to 24. At the end of the second cycle all the patients again underent a naloxone test. All patients of both groups (group A started immediately after the to cycles of HRT) ere administered naltrexone clorhydrate (Nalorex; Boehringer Biochemia Robin, Milan, Italy) at a dose of 25 mg/d for the first 7 days, and then at a dose of 50 mg/d for the next 6 months. From months 7 through 9 all subjects reduced naltrexone dosage to 25 mg/d, and then treatment as suspended. A total of 9 months of naltrexone administration as performed. The group of 10 amenorrheic patients left apart (naloxone responders: n = 5; naloxone nonresponders: n = 5) as treated ith placebo (vanilla tablets by mouth) ith the same schedule as the naltrexone treated. An accurate follo-up of each patient as performed to record the occurrence of side effects and of menstrual cyclicity. Before and after 3 and 6 months ofnaltrexone administration all patients underent a pulsatility study for LH and FSH (4 hours of blood samples every 10 minutes). If menstrual bleeding occurred, pulsatility of plasma LH as studied ithin 6 to 10 days. A further control as assessed 6 months after the complete suspension of naltrexone administration. The BMI as calculated carefully for all the patients along the period of observation. All hormonal tests ere performed by inserting an heparin ell in an antecubital vein 1 hour before commencing venous sampling. Blood samples ere centrifuged immediately and stored frozen at -20 C until assayed. None of the patients reported serious side effects apart from the feeling of nausea at the beginning of the treatment (three patients of group A and to patients of group B) and none of them discontinued the therapy. Assays All samples from the same subject ere assayed in duplicate in the same assay. Plasma LH and FSH concentrations ere determined using an immunofluorimetric assay described previously (3,4). The evaluation of the variability of LH and FSH assays ere determined on 25 replicates from a serum pool from the same individual assayed together ith the time series (3, 4). Prolactin, E2, and P plasma concentrations ere determined in to different plasma specimens ofthe pulsatility test (times 0 and 10) using commercially available RIAs (Radim; Pomezia, Rome, Italy) hose intra-assay and interassay coefficients of variation ranged beteen 4.5% and 9.2% Pulse Detection The presence of significant LH pulses as determined using the program DETECT (17), hose detection logic and characteristics have been described already (17). Data from each subject ere processed ith a P value set at 0.01 (1%) for the nominal false positive rate. The measurement error and the pa- 952 Genazzani et al. Naltrexone administration in hypothalamic amenorrhea Fertility and Sterility

3 rameters of the best variance model to use for pulse analysis ere determined on the duplicates for each time series using the program PREDETEC.WKI (17). Both programs ere developed at the Laboratory of Theoretical and Physical Biology, National Institutes of Health, Bethesda, Maryland. Statistical Analysis Presence of significant difference beteen groups as tested, after one-ay analysis of variance, using the Student's t-test for paired and unpaired data or the X 2 test as appropriate. 3oo, , A 250 ~200~ ~ II: o Z ;;;; 150- ~ :::;; 100 :s 50 o~ ~~~~~--~ RESULTS Figure 1 shos the maximum LH response to naloxone infusion, reported as percent increment from baseline in patients group A, before and after 2 months ofhrt, and in group B. After the to cycles ofhrt, 8 of 15 patients in group A shoed a significant LH response to the naloxone test. Interestingly, a higher response to naloxone infusion after HRT as observed in hypogonadotropic patients (five versus seven subjects) rather than in normogonadotropic patients (three versus eight subjects) (Fig. 1, middle). Mean E2 plasma levels (baseline: 18.0 ± 0.6 pg/ml [conversion factor to SI unit, 3.671]; mean ± SEM) increased significantly in all patients after 3 and 6 months of naltrexone therapy (45.5 ± 3.7 and 55.0 ± 5.5 pg/ml, respectively; P < 0.01 from baseline). Mean LH plasma levels increased, hereas FSH did not sho any significant change (Table 1). Placebotreated patients did not sho any significant increase of gonadotropin and E2 plasma levels. Indeed the significant difference beteen LH plasma levels remained throughout the interval of observation. Both in naltrexone- and in placebo-treated patients, subjects ith lo «3 lull) or normal (~3 lull) plasma LH levels ere randomly present. Luteinizing hormone pulse frequency did not sho any change hereas the pulse amplitude increased significantly (P < 0.05) after 3 and 6 months oftreatment and remained unchanged 6 months after naltrexone suspension (Table 1). Figure 2 shos the LH secretory pattern of one patient before and after 3 and 6 months of naltrexone therapy. Figure 3 summarizes the cumulative percent of patients ho shoed the restoration of menstrual bleeding. In 24 of 30 patients (80%), the restoration of menstrual bleeding as shon ithin 90 days from the beginning of naltrexone administration. The reduced discriminative role of the naloxone acute test to select patients to be treated ith a specific blocker of opioidergic receptors as demon- 300, B ~200~ ~~~ ~ II: o Z ;;;; 150 ~ :::;; 100 :s ~~--~--::;::::;::--#.-~ o~ ~~~~~--~ 700, c 600 o~ ~------~--~ Figure 1 Luteinizing hormone response to naloxone acute infusion (0.4 mg IV) expressed as maximum percent increase from baseline for patients of group A before (A) and immediately after to cycles of HRT (B) and for patients of group B (C). strated by the fact that no significant differences ere observed in the occurrence of menstrual bleeding beteen responders and nonresponders to naloxone test (these last ere treated ith HRT before Vol. 64, No.5, November 1995 Genazzani et al. Naltrexone administration in hypothalamic amenorrhea 953

4 Table 1 Luteinizing Hormone Pulsatile Characteristics of Amenorrheic Patients* Baseline (TO) After 3 months (T3) After 6 months (T6) 6 Months after suspension (TI2) LH Ampli- LH Ampli- LH Ampli- LH Ampli- Patients LHt peaks/4 h tude LH peaks/4 h tude LH peaks/4 h tude LH peaks/4 h tude mlulml miulml miulml miu/ml miulml miu/ml miu/ml miu/ml Naltrexone (n = 30) 3.0 ± ± ± 0.2:1: 4.0 ± ± ± ± ± ± ± ± ± 0.2 Placebo (n = 10) 3.8 ± ± ± ± ± ± ± ± ± ± ± ± 0.3 * Values are means ± SEM. t Conversion factor to SI unit, :I: P < 0.05 versus T3, T6, T12. naltrexone administration) under naltrexone administration (data not shon)_ Some patients failed to respond to naltrexone administration since no menstrual bleeding occurred. Mter 6 months of treatment all patients reduced naltrexone dosage from 50 to 25 mgld for 3 months and still maintained a normal menstrual cyclicity. Six months after naltrexone discontinuation, 75% (18/24) of patients still shoed the occurrence of menstrual cycles. Six patients ere amenorrheic upon return (Fig. 3, inset). The occurence of menstrual bleeding as significantly different from placebo-treated patients (X 2 test, P < 0.01). In fact, only three patients of the placebo-treated group shoed the occurrence of menstrual bleeding and only to of them maintained menstrual bleeding. Mter 3 months of naltrexone administration, a significant and stable increase of mean BMI as observed in amenorrheic patients (Fig. 4A). No further significant changes of BMI ere observed after discontinuation of treatment. If patients ere evaluated on the basis of the occurrence of menstrual bleeding, the BMI increased both in patients ho menstruated only during the 6 months ofnaltrexone LH lull administration (n = 6) as ell as in those ho maintained a normal cyclicity (n = 18) after naltrexone discontinuation (Fig. 4B). Those amenorrheic patients ho failed to respond to naltrexone treatment and did not sho any menstrual bleeding (n = 6) did not sho any significant increase of their BMI all along the period of observation (Fig. 4, bottom). Placebo-treated patients shoed a small increase in BMI after 6 months but it as not statistically significant (Fig. 4, bottom). DISCUSSION The present study supports that the naloxone test cannot help in the selection of amenorrheic patients to be treated ith naltrexone and demonstrates the efficacy of naltrexone in the treatment of patients ith hypothalamic amenorrhea associated ith eight loss in comparison to placebo and enforces the role of the opioidergic inhibitory tone on GnRH secretion. Until no, the treatment ith naltrexone to restore ovulatory cycles produced conflicting re- W OF PATIENTS % OF PATIENTS OCCURfIEHCEOfMENSTIlJALC'1'CI.E AFTEIl C MONlHS FAOH ~AlTREXOfrE SUSPENSION IiJ 80 ~ ~ ~ ~._ ~ f ~ : : ~ o TIME Figure 2 Luteinizing hormone spontaneous secretory pattern for one amenorrheic patient before (.), after 3 months CA), and after 6 months (.) of naltrexone administration. o W DAYS FROM THE BEGINNING OF TREATMENT Figure 3 Graphic representation of the cumulative number (left) and percent (right) of patients ho shoed the occurrence of menstrual cycles during and after naltrexone administration. Within 3 months, 24 of 30 patients shoed the first menstrual cycle. The highest rate of occurrence as in the first 50 days. Six months after naltrexone discontinuation, 75% (18/24) of the patients still shoed regular menstrual cyclicity (inset). 954 Genazzani et at. Naltrexone administration in hypothalamic amenorrhea Fertility and Sterility

30 25 20 15 10 5 0 A * * BASELINE AFTER :s MONTHS AFTER e MONTHS AFTER SUBPENSION 30,---------------------------------------, B 25 **.**. BASELINE AFTER:" MONTHS AFTER.

5 A * * BASELINE AFTER :s MONTHS AFTER e MONTHS AFTER SUBPENSION 30, , B 25 **.**. BASELINE AFTER:" MONTHS AFTER. MONTHS AneR SUSPENSION Figure 4 (A), Mean ± SEM BMI in the amenorrheic patients under study. At the 6th month oftreatment a significant increase in mean BMI as observed. (B), Mean ± SEM BMI in amenorrheic patients under naltrexone treatment according the occurrence and/or the disappearance of the menstrual cyclicity after the naltrexone or placebo discontinuation. Those ho never shoed any menstrual bleeding also failed to sho any significant change of their body eight. Menstruating (I l); no menstrual cyclicity after therapy discontinuation (1:21); no menstrual cyclicity at all (D); placebo (.). *P < 0.05 versus baseline and after 3 months. sults (9-13), but none of the previous studies evaluated the activity of the opiatergic tone by the use of naloxone test or folloed the patients as e did in the present study. Our study confirms the presence of to distinct populations of amenorrheic patients: those ho respond and those ho do not respond to acute naloxone test, as reported previously (18, 19). The evidence that 2 months of HRT recovered the ability to respond to naloxone in terms of LH plasma level increase in 8 of 15 patients (53%) confirms a certain correlation beteen E2 plasma levels and LH response to naloxone (10). In all postmenopausal omen, E2 replacement therapy restores the response to naloxone infusion (14). Using the naloxone test, a group of amenorrheic patients potentially characterized by a higher rate of probability of positive response to the chronic naltrexone administration as selected, hoever, no difference as found ith patients undergoing naltrexone administration after HRT. On the basis of these observations, the response to naloxone acute test did not help to choose a therapeutic strategy. Moreover, the 2 months of HRT did not affect the responsiveness to the longterm naltrexone administration. In fact, even if a certain amount of amenorrheic patients recovered the response to acute naloxone test immediately after HRT, no differences ere observed beteen responding and nonresponding patients in terms of occurrence of menstrual cyclicity at the end of the study. Naltrexone gave positive effects in a high percentage of patients, independently from basal LH levels, inducing menstrual bleeding ithin 30 to 90 days from the beginning of treatment in 24 of 30 patients (80%). Moreover, the efficacy of naltrexone as sustained consistently by the lack of effects of placebo to induce any relevant change of the hypothalamopituitary-gonadal (HPG) axis function. Moreover, the increased body eight that occur in all patients under treatment is of interest. In fact, all patients ere undereight and many of them shoed a significant increase in their BMI at the 6th month of treatment. Interestingly, the occurrence of menstrual cycles occurred ithin 3 months. This last observation suggests that the naltrexone has a central effect in restoring the functional activity of the hypothalamus-pituitary axis, independent from an immediate body eight gain. Conversely, it can be suggested that the restoration of a certain degree of regular HPG axis function may act on the hypothalamic centers affecting and/or regulating food intake as ell as mood and behavior. In fact, a possible role of menstrual cyclicity in affecting body eight gain is sustained by the observation that all patients ho menstruated shoed an increased BMI, hereas those ho failed to respond had no significant increase in their BMI. In conclusion, the present study shos that the use of the naloxone test to select the amenorrheic patients to be treated ith naltrexone is not helpful and demonstrates that the use of naltrexone is effective in restoring HPG axis function and menstrual cycles in patients ith hypothalamic amenorrhea associated ith eight loss. Acknoledgment. We are grateful to David Rodbard, M.D., Division of Computer Research and Technology, National Institutes of Health, Bethesda, Maryland, for kindly providing the program DETECT. REFERENCES 1. Vigersky RA, Andersen AE, Thompson RH, Lauriaux DL. Hypothalamic dysfunction in secondary amenorrhea associ- Vol. 64, No.5, November 1995 Genazzani et al. Naltrexone administration in hypothalamic amenorrhea 955

6 ated ith simple eight loss. N Engl J Med 1977;297: Berga SL, Mortola SF, Girton L, Suh B, Laughlin G, Pham P, et al. Neuroendocrine aberrations in omen ith functional hypothalamic amenorrhea. J Clin Endocrinol Metab 1989; 68: Genazzani AD, Petraglia F, Fabbri G, Monzani A, Montanini V, Genazzani AR. Evidence of luteinizing hormone secretion in hypothalamic amenorrhea associated ith eight loss. Fertil Steril 1990;54: Genazzani AD, Petraglia F, Benatti R, Montanini V, Algeri I, Volpe A, et al. Luteinizing hormone (LH) secretory burst duration is independent from LH, prolactin, or gonadal steroid plasma levels in amenorrheic omen. J Clin Endocrinol Metab 1991; 72: Genazzani AD, Petraglia F, Volpogni C, Gastaldi M, Pianazzi F, Montanini V, et al. Modulatory role of estrogens and progestins on groth hormone episodic release in omen ith hypothalamic amenorrhea. Fertil Steril 1993;60: Genazzani AD, Petraglia F, Gastaldi M, Surico N, Genazzani AR. Episodic release of prolactin in omen ith eight lossrelated amenorrhea. Gynecol Endocrinol 1994;8: Quigley ME, Sheehan KL, Casper RF, Yen SSC. Evidence for increased dopaminergic and opioid activity in patients ith hypothalamic hypogonadotropic amenorrhea. J Clin Endocrinol Metab 1980;50: Khoury SA, Reame NE, Kelch RP, Marschall JC. Diurnal patterns of pulsatile luteinizing hormone secretion in hypothalamic amenorrhea: reproducibility and responses to opiate blockade and an ll<2-adrenergic agonist. J Clin Endocrinol Metab 1987;64: Remorgida V, Venturini PL, Anserini P, Salerno E, De Cecco L. Naltrexone in functional hypothalamic amenorrhea and in the normal luteal phase. Obstet Gynecol 1990;76: Armeanu MC, Berkhout GMJ, Schoemaker J. Pulsatile luteinizing hormone secretion in hypothalamic amenorrhea, anorexia nervosa, and polycystic ovarian disease during naltrexone treatment. Fertil Steril 1992;57: Armeanu MC, Lambalk CB, Berkhout GMJ, Schoemaker J. Effects of opioid antagonism ith naltrexone on pulsatile luteinizing hormone secretion in omen ith hypothalamic amenorrhea in basal conditions and after discontinuation of treatment ith pulsatile LHRH. Gynecol Endocrinol 1992; 6: Wildt L, Leyendecker G. Induction of ovulation by the chronic administration of naltrexone in hypothalamic amenorrhea. J Clin Endocrinol Metab 1987;64: Wildt L, Leyendecker G, Sir-Petermann T, Waibel-Treber S. Treatment ith naltrexone in hypothalamic ovarian failure: induction of ovulation and pregnancy. Hum Reprod 1993;8: D'Amico JF, Greendale GA, Lu JKH, Judd HL. Induction of hypothalamic opioid activity ith trans dermal estradiol administration in postmenopausal omen. Fertil Steril1991; 55: Kletter GB, Foster CM, Beitins IZ, Marshall JC, Kelch RP. Acute effects of testosterone infusion and naloxone on luteinizing hormone secretion in normal men. J Clin Endocrinol Metab 1992; 75: American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 3rd ed. Washington, DC: American Psychiatric Association, Oerter KE, Guardabasso V, Rodbard D. Detection and characterization of peaks and estimation of instantaneous secretory rate for episodic pulsatile hormone secretion. Comput Biomed Res 1986; 19: Lightman SL, Jacobs HS, Magnuire AK, McGarrick G, Jeffcoate SL. Constancy of opioid control of luteinizing hormone in different pathophysiological states. J Clin Endocrinol Metab 1981;52: Veldhuis JD, Kulin HE, Warner BA, Santner SJ. Responsiveness of gonadotropin secretion to infusion of opiate-receptor antagonist in hypogonadotropic individuals. J Clin Endocrinol Metab 1982;55: Genazzani et a1. Naltrexone administration in hypothalamic amenorrhea Fertility and Sterility