December 9, 2020
By Maggie Musso, MD
Editor’s Note: This is a review of research[i] published twenty-five years ago in Fertility and Sterility titled, “Naltrexone treatment restores menstrual cycles in patients with weight loss-related amenorrhea.” The encouraging results of this interesting study highlight the impact of naltrexone on the hypothalamic-pituitary-gonadal (HPG) axis and point to an association between the menstrual cycle and body weight. Dr. Maggie Musso was a fourth-year medical student when she summarized this research while on the online electivetaught by FACTS cofounder, Dr. Marguerite Duane, through Georgetown University School of Medicine. Learn more about the FACTS electives and register for the spring here.
Functional hypothalamic amenorrhea (FHA) is a common source of amenorrhea, causing 20-35% of secondary amenorrhea and accounting for 3% of primary amenorrhea cases.[ii] It is defined as an absence of menses for more than 6 months with normal androgen, prolactin, thyroid, and adrenal cortex hormone levels. Common associated factors include stress, weight loss, and exercise, with neuroendocrine anomalies proposed as a key underlying pathophysiologic mechanism. This study by Genazzani et al evaluates treatment of weight loss-related amenorrhea with naltrexone.
This study involved 40 women with functional hypothalamic amenorrhea, a body mass index (BMI) below 20, and a history of weight loss in the previous 18 months. Exclusion criteria included psychiatric diseases and intense physical training. Patients were first divided into two groups — responders and non-responders — based on luteinizing hormone (LH) response to naloxone infusion. A group consisting of 5 non-responders and 5 responders served as a control group. The non-responders received two cycles of hormone replacement therapy.
Following this initial treatment, naloxone testing was repeated in both groups. At that point, patients in both groups were treated with naltrexone (25 mg/day for 7 days, then 50 mg/day for 6 months, then 25 mg/day during months 7-9, then discontinued). LH and follicle stimulating hormone (FSH) pulsatility studies were completed at months 3 and 6, as well as 6 months after discontinuation of naltrexone.
In this study, naltrexone treatment improved various endpoints assessed, including hormone levels, amenorrhea, and BMI. Of the 30 patients treated with naltrexone, 80% experienced restoration of menses within 90 days. Six months after discontinuation of naltrexone, 75% of patients continued to have menstrual cycles. Notably, no significant difference was found in the occurrence of menses when comparing responders and non-responders to the naloxone test. Average estradiol levels increased significantly in all patients after 3 and 6 months of treatment with naltrexone.
Average LH levels also demonstrated an increase. LH pulse amplitude increased significantly with treatment and was maintained 6 months after discontinuation. LH pulse frequency, on the other hand, showed no change, and there was no significant change in FSH levels.
Mean BMI increased significantly after naltrexone treatment. This increase occurred in women who had loss of menstruation following discontinuation of treatment and in women who maintained menstruation. Non-responders to naltrexone did not show a significant increase in BMI.
In summary, this study demonstrates the efficacy of naltrexone to treat functional hypothalamic amenorrhea associated with weight loss, providing further evidence for a relationship between the opioid system and the hypothalamic-pituitary-gonadal axis. The findings also suggest that naloxone cannot be used to select patients who will respond to naltrexone treatment, although it can be used to define distinct populations of patients with amenorrhea. Furthermore, the increased BMI seen in patients who responded to naltrexone suggests the menstrual cycle may influence body weight. The finding that some patients responded to naltrexone prior to a change in BMI suggests naltrexone may exert an independent effect on the HPG axis.
Strengths of this study include its design as a randomized control trial, unique evaluation of patient responsiveness to naloxone, and extended follow-up. The study is primarily limited by its small sample size.
Naltrexone has been found to be an effective treatment for FHA in several studies.[iii],[iv],[v] However, all of these studies are more than twenty years old. Despite evidence of a relationship between the opioid system and the HPG axis,[vi],[vii] no new studies investigating naltrexone as a treatment option for FHA have been published, and treatment of FHA with naltrexone has not become standard practice.[viii]
Given the findings in the existing literature pointing to its efficacy and safety, future research should revisit naltrexone treatment for FHA and assess its ability to restore menstrual cyclicity in a larger and diverse sample of women. In addition, studies should investigate the use of fertility awareness-based methods (FABMs) to provide targeted treatment with naltrexone in FHA, and the ability of FABMs to improve diagnosis and treatment of primary and secondary amenorrhea. Given the impact of FHA on fertility as well as bone, cardiovascular, and reproductive health, effective treatments for this condition are of critical importance.
[i] Genazzani AD, Petraglia F, Gastaldi M, Volpogni C, Gamba O, Genazzani AR. Naltrexone treatment restores menstrual cycles in patients with weight loss-related amenorrhea. Fertility and Sterility. 1995;64(5):951-956.
[ii] Golden NH, Carlson JL. The Pathophysiology of Amenorrhea in the Adolescent. Annals of the New York Academy of Sciences. 2008;1135(1):163-178. doi:10.1196/annals.1429.014.
[iii] Remorgida V, Venturini PL, Anserini P, Salerno E, De Cecco L. Naltrexone in functional hypothalamic amenorrhea and in the normal luteal phase. Obstetrics & Gynecology. 1990;76:1115-1120.
[iv] Leyendecker G, Waibel-Treber S, Wildt L. Pulsatile administration of gonadotrophin releasing hormone and oral administration of naltrexone in hypothalamic amenorrhoea. Human Reproduction. 1993;8(Suppl 2): 184-188.
[v] Roozenburg BJ, van Dessel HJ, Evers JL, Bots RS. Successful induction of ovulation in normogonadotrophic clomiphene resistant anovulatory women by combined naltrexone and clomiphene citrate treatment. Human Reproduction 1997;12:1720-2.
[vi] Böttcher B, Seeber B, Leyendecker G, Wildt L. Impact of the opioid system on the reproductive axis. Fertil Steril. 2017;108(2):207-213.
[vii] Vuong C, Van uum SH, O’dell LE, Lutfy K, Friedman TC. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev. 2010;31(1):98-132.
[viii] Gibson ME, Fleming N, Zuijdwijk C, Dumont T. Where Have the Periods Gone? The Evaluation and Management of Functional Hypothalamic Amenorrhea. J Clin Res Pediatr Endocrinol. 2020;12(Suppl 1):18-27.
Author Bio: Maggie Musso, MD developed a passion for serving people with mental illness while earning a BA in theology at the University of Notre Dame. As a senior, she was honored with the 2016 Student Voice of Mental Health Award. She earned her medical degree at the Loyola University Stritch School of Medicine along with an MA in bioethics and health policy. She is now a psychiatry resident at Case Western Reserve University/University Hospitals.
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