ANISHA SINGH, BS
SUMMARY POINTS
Mu-opioid receptors are found in a variety of organs that can influence fertility, such as the endometrium, oocytes, granulosa cells, and the hypothalamus-pituitary-gonadal axis.
Opioid-consuming females reported decreased LH, FSH, GnRH, DHEA, progesterone, estrogen, and testosterone levels
Opioid-consuming females faced problems with normal reproductive processes due to the impacts of opioids on the body. Issues included amenorrhea, sexual dysfunction, hypogonadism, hypothyroidism, abnormal or ceased menses, and decreased rate of conception.
ANALYSIS
Background
In the last few decades, opioid use and misuse have created an ongoing global epidemic that has affected the lives of many. The United States (US) has been a major epicenter of this epidemic, constituting only 4.4% of the world’s population but consuming over 80% of the world’s opioids [1]. In the US, among women of reproductive age, one in every six women is prescribed opioids annually [2]. In 2020, 9.5 million people aged 12 or older misused opioids. The most represented age group consisted of those between 18 and 25 years old, followed by individuals aged 26 years or older [3]. As a result, opioid use is highly prevalent amongst the reproductive population.
Opioids affect the brain and the central nervous system through the mu-opioid receptors found in multiple organs of the reproductive system. For example, opioid receptors are seen on the endometrium in the uterus, which when activated can result in a lack of proper luminal epithelial differentiation, stromal cell proliferation, and angiogenesis [4]. Thus, opioids can impact the endometrium’s ability to receive and implant a fertilized egg. Opioid receptors are also found on oocytes and granulosa cells [4,5]. Additionally, mu-opioid receptors are found on integral components of the endocrine system that impact fertility, such as the hypothalamus-pituitary-gonadal axis. Opioids bind to receptors on this axis directly affecting the production of gonadotropin-releasing hormone (GnRH), and indirectly affecting the downstream hormone products follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (Figure 1) [4,5,6]. LH regulates ovulation, maintains the menstrual cycle, and promotes progesterone production for endometrial growth, egg implantation, and maturation of primordial germ cells [7]. FSH promotes estrogen production and follicular development, and thus impacts the proper maturation and release of the egg for fertilization and implantation [8]. Another important hormone integral to fertility is dehydroepiandrosterone (DHEA). DHEA helps produce testosterone and estrogen, improves ovarian function, promotes follicle growth, reduces follicle atresia, and reduces rates of aneuploidy [9]. Lastly, estrogen, progesterone, and other sex hormones also help regulate the proper growth, development, and function of the reproductive system [9]. As a result, the wide array of opioid receptors holds the capacity and potential to cause altered organ function and difficulties in normal reproductive processes, such as fertility. This analysis aims to explore how these opioid receptors influence a woman’s ability to conceive, and the extent to which normal reproductive processes are impacted.
Figure 1: A flowchart depicting some of opioids’ effects on the structures and hormones of the pituitary-hypothalamus-gonadal axis. GnRH: gonadotropin-releasing hormone; CRH: corticotropin-releasing hormone; LH: luteinizing hormone; FSH: follicle-stimulating hormone; ACTH: adrenocorticotropic hormone; DHEAS: dehydroepiandrosterone sulfate. Reprinted from Marudhai S, Patel M, Valaiyaduppu Subas S, et al. Long-term opioids linked to hypogonadism and the role of testosterone supplementation therapy. Cureus. 2020;12(10): e10813. doi:10.7759/cureus.10813
Findings
The intersection of research involving opioid use and female reproductive health has significantly expanded in the last decade as more opioid-related health risks have become known. Daniell studied opioid use in premenopausal women ages 30–50 years old and found a 48-57% decrease in testosterone, estrogen, and DHEA sulfate levels, and a 30% decrease in LH and FSH hormone values in the opioid-consuming group compared to the control group. [10] Furthermore, a 32% increase in the rate of nonsurgical amenorrhea was seen in opioid-consuming women compared to the control group (52% versus 20% respectively) [10]. Over the course of the sustained-acting opioid therapy, many women also reported lower body mass indexes, altered or ceased menses, and hypogonadism [10]. Rhodin et al. reinforced these results by illustrating how the opioid-consuming group in the study was found to have decreased estradiol levels, a lower LH peak (Figure 2), decreased rate of normal menstruation, increased rate of sexual dysfunction, and a lower DHEA mean value. Additionally, 5 new cases of hypothyroidism were seen in the opioid-consuming group [11]. Flannagan et al. studied how opioid use influenced conception rates and found that women who consumed opioids during preconception were 29% less likely to become pregnant compared to those who had not consumed opioids [12].
Figure 2: How LH values change over time after GnRH stimulation. Reprinted from: Rhodin A, Stridsberg M, Gordh T. Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment. Clin J Pain. 2010;26(5):374-380. doi:10.1097/AJP.0b013e3181d1059d
Discussion
Opioid use has the potential to cause decreased fertility and increased pregnancy risks. These complications result from the suppression of the hypothalamic-pituitary-gonadal axis and impairment of the function of critical reproductive organs. However, much remains unknown regarding the full influence opioids have on the reproductive system. Future studies are needed to better understand the cellular mechanisms involved in opioids' effects on reproductive function and their implication in individuals with pre-existing reproductive health conditions, such as endometriosis and polycystic ovarian syndrome. Additionally, studies looking at the effect specific opioid medications and dosages have on fertility are needed. Healthcare professionals should consider individual reproductive and endocrine health when prescribing opioids to patients and weigh the advantages and disadvantages of opioids on a case-by-case basis.
REFERENCES
Injury, Violence Prevention. Indicator dashboards opioid dashboard prescribing practices perception of pain - Minnesota department of health. Published online 2018. Accessed June 30, 2022. https://www.health.state.mn.us/communities/opioids/prevention/painperception.html
Cdc.gov. Accessed June 30, 2022. https://www.cdc.gov/drugoverdose/pdf/pubs/2019-cdc-drug-surveillance-report.pdf.
2020 national survey of drug use and health (NSDUH) releases. Samhsa.gov. Accessed June 30, 2022. https://www.samhsa.gov/data/release/2020-national-survey-drug-use-and-health-nsduh-releases
Böttcher B, Seeber B, Leyendecker G, Wildt L. Impact of the opioid system on the reproductive axis. Fertil Steril. 2017;108(2):207-213. doi:10.1016/j.fertnstert.2017.06.009
Tang X, Chen Y, Ran H, et al. Systemic morphine treatment derails normal uterine receptivity, leading to embryo implantation failure in mice. Biol Reprod. 2015;92(5):118. doi:10.1095/biolreprod.115.128686
Roa J, Herbison AE. Direct regulation of GnRH neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice. Endocrinology. 2012;153(11):5587-5599. doi:10.1210/en.2012-1470
Nedresky D, Singh G. Physiology, Luteinizing Hormone. In: StatPearls [Internet]. StatPearls Publishing; 2021.
Orlowski M, Sarao MS. Physiology, follicle stimulating hormone. In: StatPearls [Internet]. StatPearls Publishing; 2022.
Gleicher N, Barad DH. Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR). Reprod Biol Endocrinol. 2011;9(1):67. doi:10.1186/1477-7827-9-67
Daniell HW. Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. J Pain. 2008;9(1):28-36. doi:10.1016/j.jpain.2007.08.005
Rhodin A, Stridsberg M, Gordh T. Opioid endocrinopathy: a clinical problem in patients with chronic pain and long-term oral opioid treatment. Clin J Pain. 2010;26(5):374-380. doi:10.1097/AJP.0b013e3181d1059d
Flannagan KS, Mumford SL, Sjaarda LA, et al. Is opioid use safe in women trying to conceive? Epidemiology. 2020;31(6):844-851. doi:10.1097/EDE.0000000000001247
Marudhai S, Patel M, Valaiyaduppu Subas S, et al. Long-term opioids linked to hypogonadism and the role of testosterone supplementation therapy. Cureus. 2020;12(10):e10813. doi:10.7759/cureus.10813
Joseph R. Case challenge: Chronic opioid use causing adrenal insufficiency. PPM Pro. Published July 14, 2014. Accessed June 30, 2022. https://www.practicalpainmanagement.com/treatments/pharmacological/opioids/case-challenge-chronic-opioid-use-causing-adrenal-insufficiency