Drugs & Hormones: How Common Prescriptions Impact the Endocrine System

CARRIE JONES, ND, FABNE, MPH

Do medications affect hormones? Absolutely! Considering the escalating number of drugs prescribed in the United States, this relationship is a significant cause for concern. The National Ambulatory Medical Care Survey (NAMCS) found that between 2014 and 2016, 2.9 billion drugs were ordered or prescribed by physician offices in the United States.¹ Approximately 46% of adult men and women are taking at least 1 prescription medication, while 22% are taking 3 or more.² In this survey, the most prescribed classes of prescription drugs included analgesics, anti-hyperlipidemic agents, and dermatologic agents, including steroid creams. Birth control also ranked high among prescription drugs ordered.¹ Unfortunately, regardless of the intent of use, many of these medications have profound effects on the endocrine system. 

Pharmaceutical Culprits 

Analgesics 

Analgesics are prescription drugs used to control pain. One particularly potent subclass of analgesics includes the opioid family. Drugs in this class not only reduce pain and create a sense of euphoria, but are also known to be potentially addictive and can cause very serious side effects. In fact, the Centers for Disease Control and Prevention (CDC) reports that almost 70% of drug overdose deaths involve opioids, and usually fentanyl is the culprit.³ In the endocrine system, opioids have been shown to induce hypogonadism in both men and women.⁴ They can suppress gonadotropin-releasing hormone (GnRH) from the hypothalamus, thereby lowering both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and the subsequent downstream hormones in the ovaries and gonads.^4,5 When taken acutely, opioids can temporarily increase corticotropin-releasing hormone (CRH) from the hypothalamus and adrenocorticotropic hormone (ACTH) from the pituitary gland, resulting in increased cortisol. Over time, these stress hormones begin to decline due to the cortisol negative feedback loop with the brain.⁶ Ovarian, testicular, and adrenal suppression appear to be dependent on the dose and length of time that the meds are taken; however, this varies from person to person. 

Steroids 

Steroid medications are used in a variety of settings to reduce inflammation. Physicians prescribe them as injections, oral tablets, nasal sprays, inhalers, and topical creams. Synthetic glucocorticoids (like prednisone) should not be confused with cortisol (such as hydrocortisone). The synthetic glucocorticoids are significantly more potent and long-acting compared to their cortisol counterpart, and they tend to cause much more hypothalamic-pituitary-adrenal (HPA) axis suppression.⁷ Daniel Becker sums it up well when he says, “While a patient is consuming a daily exogenous source of glucocorticoid, the patient’s adrenal cortex does not function, and this results in varying degrees of adrenal atrophy. This becomes a concern for patients receiving more than 15 mg/d of prednisone or its equivalent for longer than 3 weeks. The influence of smaller doses over longer durations is highly variable.”⁸ While this is certainly a concerning side effect to be aware of, glucocorticoid treatment should also not be stopped abruptly. Rather, treatment should always be tapered off in some fashion to prevent an HPA crash. 

What about HPA axis suppression in patients taking cortisol (eg, hydrocortisone)? Physiologically, the adult human makes approximately 15-20 mg of cortisol in the adrenal gland. More can be created by way of the 11beta-HSD1 enzyme, which activates cortisone into cortisol in various tissues. In a study in which patients were given a single 20 mg dose of oral hydrocortisone, peak supraphysiologic levels of cortisol were shown to occur at 2 hours in serum, saliva, and urine.⁹ The levels then declined over 5-6 hours. The authors of the study concluded that 20 mg of hydrocortisone was excessive for routine maintenance, as this dose was supraphysiologic.⁹ Given the known negative feedback loop that occurs with excessive cortisol, it is possible that routine supraphysiologic doses could suppress the HPA axis.¹⁰ 

Do glucocorticoids affect the thyroid axis? A study conducted in 2014 looked at people who received 20 mg of prednisone for 9 days.¹¹ The results revealed a significant decrease in the mean serum TSH level, but showed no changes in thyroxine (T4), triiodothyronine (T3), or thyroxine-binding globulin (TBG). It is well known that glucocorticoids are often given to patients during a thyroid storm to suppress TSH production, prevent the conversion of T4 into the active T3, and also reduce inflammation.¹² Therefore, it is advisable to monitor thyroid labs when a patient is on glucocorticoids. 

Oral Isotretinoin 

Dermatologic agents often include the acne medication, isotretinoin. This medication is a teratogen, pregnancy category X, and comes with a host of known side effects, including depression, anxiety, suicidal ideation, pseudotumor cerebri, pancreatitis, hearing impairment, visual impairment, irritable bowel disease, headaches, and many more.¹³ While the exact mechanism is unknown, it is thought to inhibit sebaceous gland function and keratinization to reduce moderate-to-severe acne.¹³ Unfortunately, isotretinoin also greatly affects the endocrine system. Human studies have shown that it can decrease free T3, TSH, and TSH receptor antibody, LH, prolactin, total testosterone, morning cortisol, and ACTH.^14,15 Even a European Union Scientific advisory committee found that the agent can decrease testosterone, thereby lowering libido and even causing erectile dysfunction.¹⁶ Therefore, when someone is on isotretinoin or reports they were “never well since using it,” consider hormone testing to confirm. 

Contraceptives 

Lastly, prescriptions for the hormonal birth control pill are intended to suppress the hypothalamic-pituitary-ovarian (HPO) axis. The standard combined oral contraceptive consists of both progestin and conjugated equine estrogens (CEE), taken daily for 3 weeks, followed by a week of placebo pills that trigger what is known as “breakthrough bleeding,” induced by the sudden drop in hormones. Although the outward appearance is the same as a natural menstrual cycle (menstrual bleeding in week 1 of a 28-day cycle), the constant high levels of a progestin and CEE in a woman taking the pill actually abolish the normal hormonal cycling that underlies ovulation. Because of the intricate feedback loops controlling the menstrual cycle, artificially altering 1 or 2 hormones can affect the entire cycle. This fundamental knowledge has been used both to suppress the cycle (with the goal of contraception) and to stimulate ovulation (with the hopes of promoting fertility), depending on how exogenous hormones are utilized. The synthetic progestin used in the birth control pill causes a negative feedback loop to the brain, resulting in decreased GnRH from the hypothalamus, and decreased LH and FSH from the pituitary. This inhibits follicle development, ovulation, and endogenous production of estradiol and progesterone. Another side effect of the oral synthetic estrogen is the increase in binding globulins. This includes TBG and sex hormone-binding globulin (SHBG). An increase in TBG can lower circulating thyroid hormones, while an increase in SHBG can lower circulating testosterone and other androgens.¹⁷  

Besides the birth control pill, the progestin-only intrauterine device (IUD) could also affect ovulation and progesterone levels in some women. The IUD is thought to prevent pregnancy by thinning the lining of the endometrium in order to prevent implantation and alter cervical mucus to prevent sperm passage.^18,19 In addition, research has shown that 55% of women using the progestin-IUD did not ovulate during a 1-year study, while 25% still did not ovulate after 4 years.¹⁹ Anovulation results in no corpus luteum formation, thus no progesterone production. 

Closing Comments 

This article is a small representation of commonly prescribed medications to illustrate the profound effect they can have on the endocrine system. As “hormonal complaints” are common reasons that patients seek naturopathic care, it is important to get a full accounting of patients’ medications, including over-the-counter ones, to evaluate their full effect on each axis. The reason for a patient’s symptoms could very well lie in that harmless-looking pill bottle. 

References: 

1. Rui P, Okeyode T. National Ambulatory Medical Care Survey: 2016 National Summary Tables. Available at: https://www.cdc.gov/nchs/data/ahcd/namcs_summary/2016_namcs_web_tables.pdf?source=post_page. Accessed September 10, 2020. 
2. Martin CB, Hales CM, Gu Q, Ogden CL. Prescription Drug Use in the United States, 2015–2016. NCHS Data Brief No. 334, May 2019. CDC Web site. https://www.cdc.gov/nchs/products/databriefs/db334.htm. Accessed September 10, 2020.  
3. Centers for Disease Control and Prevention. Opioid Basics. Last reviewed March 19, 2020. CDC Web site. https://www.cdc.gov/drugoverdose/opioids/index.html. Accessed September 10, 2020. 
4. Baillargeon J, Raji MA, Urban RJ, et al. Opioid-Induced Hypogonadism in the United States. Mayo Clin Proc Innov Qual Outcomes. 2019;3(3):276-284. 
5. Reddy RG, Aung T, Karavitaki N, Wass JA. Opioid induced hypogonadism. BMJ. 2010;341:c4462. 
6. Seyfried O, Hester J. Opioids and endocrine dysfunction. Br J Pain. 2012;6(1):17-24.  
7. Nicolaides NC, Pavlaki AN, Maria Alexandra MA, Chrousos GP. Glucocorticoid Therapy and Adrenal Suppression. 2018 Oct 19. In: Feingold KR, Anawalt B, Boyce A, et al. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc; 2000.  
8. Becker DE. Basic and clinical pharmacology of glucocorticosteroids. Anesth Prog. 2013;60(1):25-31; quiz 32. 
9. Jung C, Greco S, Nguyen HH, et al. Plasma, salivary and urinary cortisol levels following physiological and stress doses of hydrocortisone in normal volunteers. BMC Endocr Disord. 2014;14:91. 
10. Kay SM. Pediatric Adrenal Gland Disorders. Updated February 6, 2020. Medscape Web site. https://emedicine.medscape.com/article/940347-overview#a3. Accessed September 10, 2020. 
11. Jensen J, Nolan G, Jubiz W. The effect of prednisone on serum thyrotropin, thyroxine and triiodothyronine concentrations in hypothyroid patients. J Endocrinol Invest. 2014;1(2):171-173. 
12. Misra M. Thyroid Storm Medication. Updated March 16, 2020. Medscape Web site. https://emedicine.medscape.com/article/925147-medication. Accessed September 10, 2020. 
13. Roche Laboratories. Accutane (Isotretinoin capsules). November 2008. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018662s059lbl.pdf. Accessed September 10, 2020. 
14. Karadag AS, Takci Z, Ertugrul DT, et al. The effect of different doses of isotretinoin on pituitary hormones. Dermatology. 2015;230(4):354-359. 
15. Karadag AS, Ertugrul DT, Tutal E, Akin KO. Isotretinoin influences pituitary hormone levels in acne patients. Acta Derm Venerol. 2011;91(1):31-34. 
16. European Medicines Agency. Annex I: CMDH scientific conclusions – Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisation(s). August 2017. Available at: https://tinyurl.com/y4awwvqy. Accessed May 17, 2019. 
17. Panzer C, Wise S, Fantini G, et al. Impact of oral contraceptives on sex hormone‐binding globulin and androgen levels: a retrospective study in women with sexual dysfunction. J Sex Med. 2006;3(1):104-113. 
18. Bayer Healthcare Pharmaceuticals. Mirena (Levonorgestrel-releasing intrauterine device). July 2008. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021225s019lbl.pdf. Accessed September 10, 2020. 
19. Bayer Healthcare Pharmaceuticals. Mirena. [Full prescribing information] Available at:https://www.mirena.com/html/pdf/Mirena_Prescribing_Information.pdf. Accessed September 10, 2020. 

Carrie Jones, ND, FABNE, MPH is an internationally recognized speaker, consultant, and educator on the topics of women’s health and hormones. Dr. Jones graduated from the National University of Natural Medicine in Portland, OR, where she also completed her 2-year residency in women’s health, hormones, and endocrinology. Later, she graduated from Grand Canyon University’s Master of Public Health program. Recently, she became board certified through the American Board of Naturopathic Endocrinology. She was adjunct faculty, teaching gynecology and advanced endocrinology/fertility. Currently, Dr. Jones is the Medical Director for Precision Analytical Inc, creators of the DUTCH hormone test.