by Sara Gottfried, MD and Melissa Blake, BSc, ND
Hormones drive the many functions of our body and mind. For example, hormones and their receptors influence metabolic function, heart rate, appetite, tissue growth, and development. Ultimately, the body relies on the hormonal signals of a strikingly choreographed endocrine system. Most of the endocrine system is regulated by the hypothalamic-pituitary-adrenal-thyroid-gonadal (HPATG) axis, which is instrumental in regulating mood, reproductive health, and general homeostasis.1 Unfortunately, the HPATG axis is remarkably sensitive to endocrine disruption. Chronic and stressful activation of the HPATG axis may lead to the disruption within the endocrine system. Environmental, lifestyle, and genetic factors influence the delicate balance of a well-functioning HPATG axis and impact adrenal, thyroid, and sex hormone levels.
This article will discuss the influence of oral contraceptive pills (OCPs), aka birth control pills, on the HPATG axis, since “the pill” is one of the most common iatrogenic causes of endocrine disruption. For clarity, we will discuss the various female target tissues separately—adrenal glands (via hypothalamic-pituitary-adrenal axis), thyroid (via hypothalamic-pituitary-thyroid axis), and ovaries (via hypothalamic-pituitary-gonadal axis)—though we know these systems are interdependent. As clinicians seeking to minimize risk to our patients with prescriptions, we must understand the connections between OCP use and its impact on the HPATG axis.
OCP uses and associated conditions
Combined OCPs (i.e., estrogen + progesterone) are commonly used to prevent pregnancy. Studies show roughly 80% of sexually active women report current or previous OCP use.2,3 Aside from contraception, birth control pills have also been used as a blanket therapy for many hormonally driven issues, ranging from primary dysmenorrhea to acne and polycystic ovary syndrome (PCOS). In fact, more than 50% of women on birth control pills are taking them for reasons other than contraception.4 OCPs are prescribed, mostly off label, for acne, hirsutism, painful periods (dysmenorrhea, including endometriosis), irregular menstruation, heavy periods (menorrhagia), and improvement in premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). There are also proven benefits of OCP use in terms of reduced risk of ovarian, endometrial, and thyroid cancer.5-7
Even with their utility, the high rates of OCP use underscore the importance of understanding the upstream and downstream clinical consequences for our female patients. As aforementioned, birth control pills are often given as a combination of estrogen and progesterone analogues (ethinyl estradiol and a progestin),8 but these hormones differ from the body’s natural hormones, contributing to the underdiscussed side effects associated with birth control pills.9
Estrogen is a particularly influential hormone. Both hyper- and hypo-estrogenic states are linked to acute and chronic diseases in women.10 The expected estrogen-deficient states during the menopausal transition are associated with an increased susceptibility to cardiometabolic disorders such as obesity, diabetes, and cardiovascular disease.11 Estrogen-mimicking chemicals in our environment, including synthetic hormone sources found in OCPs, have made estrogen dominance increasingly common. Estrogen dominance negatively contributes to conditions such as breast cancer, ovarian cancer, PCOS, and infertility.10 The effects of estrogen extend beyond what are traditionally considered “estrogen-responsive” tissues.
The progesterone component of birth control pills work to prevent pregnancy by inhibiting ovulation, increasing cervical mucus thickness, and preventing implantation.8 These effects, although desirable in terms of contraception, have significant impact on the endocrine system, particularly the hypothalamic-pituitary-gonadal (HPG) axis, as discussed below.
OCP influence on hypothalamic-pituitary-adrenal (HPA) axis
The HPA axis influences many physiological functions, and short-term HPA stimulation is required for a healthy stress response. Using birth control pills can cause maladaptive HPA axis reactions.
Studies demonstrate that women on OCPs have higher resting cortisol concentrations and a blunted cortisol response to stressors, such as exercise or emotional stress.12,13 Compared to women not on hormonal therapy, birth control pill users exhibited significantly altered cortisol rhythms—with lower levels upon awakening, delayed peaks, and higher overall levels.13
A dysregulated stress response is common in many conditions including autoimmune, inflammatory, and neuropsychiatric disorders.14-17 High cortisol levels contribute to anxiety and depression and negatively impact learning and memory.18,19
Monitoring and addressing HPA axis dysregulation offers an effective strategy to reduce the impact of OCP use.
OCP influence on hypothalamic-pituitary-thyroid (HPT) axis
A strong connection exists between the thyroid gland and ovaries, with thyroid hormones playing an important role in reproductive health.20
Oral estrogen therapy, such as OCP use, raises circulating levels of thyroxine-binding-globulin (TBG), a protein that binds free thyroid hormones.21 The result is a net decrease in the bioavailability of circulating thyroxine (T4), which may necessitate an increase in thyroid medication for women concurrently treated for hypothyroidism.22 Studies also show that women on birth control pills may have enlarged thyroid glands, regardless of their thyroid-stimulating-hormone (TSH) levels.23
OCP-driven nutrient deficiencies can also impact thyroid health. Thyroid function depends on zinc and selenium, which are commonly depleted micronutrients in women taking OCPs.3 Poor thyroid functioning is associated with diverse symptoms including fatigue, weight gain, constipation, depression, and cardiovascular disease.24-26
OCP use has a significant impact on thyroid function, so monitoring thyroid labs and symptomology is prudent in women using birth control pills.
Sara Gottfried, MD is a board-certified gynecologist and physician scientist. She graduated from Harvard Medical School and the Massachusetts Institute of Technology and completed residency at the University of California at San Francisco. Over the past two decades, Dr. Gottfried has seen more than 25,000 patients and specializes in identifying the underlying cause of her patients’ conditions to achieve true and lasting health transformations, not just symptom management.
Dr. Gottfried is the President of Metagenics Institute, which is dedicated to transforming healthcare by educating, inspiring, and mobilizing practitioners and patients to learn about and adopt personalized lifestyle medicine. Dr. Gottfried is a global keynote speaker who practices evidence-based integrative, precision, and Functional Medicine. She recently published a new book, Brain Body Diet, and has also authored three New York Times bestselling books: The Hormone Cure, The Hormone Reset Diet, and Younger.
Melissa Blake, BSc, ND is the Manager of Curriculum Development at Metagenics. Dr. Blake completed her pre-medical studies at Dalhousie University in Halifax, Nova Scotia and obtained her naturopathic medical training from the Canadian College of Naturopathic Medicine. Dr. Blake has over 10 years of clinical experience, specializing in the integrative and functional management of chronic diseases.
OCP influence on hypothalamic-pituitary-gonadal (HPG) axis
OCP users commonly report symptoms of sexual dysfunction, such as low libido, vaginal dryness, vulvodynia, and dyspareunia.27,28 These symptoms, experienced by about one in five patients, are most likely the result of lower testosterone levels.
OCPs impact testosterone in two ways. First, birth control pills produce an overall anti-gonadotropic effect, mostly due to the influence of progestin.8 The inhibitory effect on the HPG axis not only prevents ovulation but reduces testosterone production by more than 60%.29 OCPs have also been shown to increase sex hormone-binding globulin (SHBG) four times the level seen in non-users.35 When bound to SHBG, sex hormones are inactive and not biologically available. Thus, when there is more SHBG present, there is less free testosterone (T) available for use.30 Due to the SHBG increase, OCP may decrease free T levels twice as much as total testosterone.29 These influences on testosterone help explain some OCP side benefits (e.g., acne management, PCOS management), as well as certain side effects (i.e., sexual dysfunction, muscle loss).31-34
Importantly, clinicians need to understand that discontinuing the OCP may not reverse the reduction in testosterone activity. One study found, in women with sexual dysfunction, SHBG changes in “discontinued-users” did not decrease to values consistent with “never-users”, even after 4 months or longer.35 Prospective research is needed to answer the method of action. For example, could prolonged exposure to the synthetic estrogens in OCPs induce gene imprinting and increase gene expression of SHBG in the liver in certain women? In any case, healthcare providers need be aware of the potential long-term sexual, metabolic, and mental health consequences that can result from chronic SHBG elevation.
The HPATG axis plays diverse, crucial roles in our homeostasis, the body’s ultimate desire to maintain equilibrium. Evidence suggests that birth control pills disrupt this balance in myriad ways. Perhaps most important, be aware that discontinuation of OCPs may not completely or immediately resolve perturbations of HPATG homeostasis, such as testosterone production and activity due to changes in SHBG. Understanding the impact of OCPs offers clinicians a root-cause approach to support patients presenting with symptoms of adrenal, thyroid, and gonadal dysfunction.
- Hiller-Sturmhöfel S et al. The endocrine system: an overview. Alcohol Health Res World. 1998;22(3):153-164.
- Kavanaugh ML et al. Contraceptive method use in the United States: trends and characteristics between 2008 and 2014. Contraception. 2018;97(1):14–21.
- Daniels K et al. Contraceptive methods women have ever used: United States, 1982–2010. Natl Health Stat Rep. 2013;62:1-15.
- Guttmacher Institute. Jones R. Beyond birth control: the overlooked benefits of oral contraceptive pills. https://www.guttmacher.org/report/beyond-birth-control-overlooked-benefits-oral-contraceptive-pills. Accessed June 11, 2019.
- Wu L et al. Linear reduction in thyroid cancer risk by oral contraceptive use: a dose–response meta-analysis of prospective cohort studies. Hum Reprod. 2015;30(9):2234–2240.
- La Vecchia C. Ovarian cancer: epidemiology and risk factors. Eur J Cancer Prev. 2016;26(1):55–62.
- Caserta D et al. Combined oral contraceptives: health benefits beyond contraception. Panminerva Med. 2014;56(3):233-244.
- Regidor PA. The clinical relevance of progestogens in hormonal contraception: present status and future developments. Oncotarget. 2018;9(77):34628–34638.
- Metagenics Institute. Storoschuk B. The undiscussed side effects of birth control pills: nutrient depletions, gut dysbiosis, depression, endocrine effects, and more. https://www.metagenicsinstitute.com/blogs/birth-control-pill/. Accessed May 5, 2019.
- Patel S et al. Estrogen: the necessary evil for human health, and ways to tame it. Biomed Pharmacother. 2018;102:403-411.
- Clegg D et al. Sex hormones and cardiometabolic health: role of estrogen and estrogen receptors. Endocrinology. 2017;158(5):1095-1105.
- Boisseau N et al. Oral contraception but not menstrual cycle phase is associated with increased free cortisol levels and low hypothalamo-pituitary-adrenal axis reactivity. J Endocrinol Invest. 2013;36(11):955-964.
- Roche DJ et al. Hormonal contraceptive use diminishes salivary cortisol response to psychosocial stress and naltrexone in healthy women. Pharmacol Biochem Behav. 2013;109:84–90.
- Oyola M et al. Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity. Stress. 2017;20(5):476-494.
- Akcali A et al. Fatigue in multiple sclerosis: is it related to cytokines and hypothalamic-pituitary-adrenal axis? Mult Scler Relat Disord. 2017;15:37-41.
- De Bucy C et al. Health-related quality of life of patients with hypothalamic-pituitary-adrenal axis dysregulations: a cohort study. Eur J Endocrinol. 2017;177(1):1-8.
- Herriot H et al. Intra-individual cortisol variability and low-grade inflammation over 10 years in older adults. Psychoneuroendocrinology. 2017;77:141-149.
- Hertel J et al. Evidence for stress-like alterations in the HPA-axis in women taking oral contraceptives. Sci Rep. 2017;7(1):14111.
- Merz CJ. Oral contraceptive usage alters the effects of cortisol on implicit fear learning. Horm Behav. 2012;62(4):531-538.
- Cho MK. Thyroid dysfunction and subfertility. Clin Exp Reprod Med. 2015;42(4):131-135.
- Medau HJ et al. Serum level of thyroxin-binding globulin under oral contraception (author’s transl). Klin Wochenschr. 1975;53(15):727-729. [Article in German]
- Mazer NA. Interaction of estrogen therapy and thyroid hormone replacement in postmenopausal women. Thyroid. 2004;14(1):S27-S34.
- Garcia TS et al. Thyroid volume and Doppler evaluation of inferior thyroid artery in ultrasound: Comparison between current and previous users of oral contraceptives. J Clin Ultrasound. 2015;43(5):312-317.
- Udovcic M et al. Hypothyroidism and the heart. Methodist Debakey Cardiovasc J. 2017;13(2):55-59.
- Mullur R et al. Thyroid hormone regulation of metabolism. Physiol Rev. 2014;94(2):355–382.
- Raps M. Thyroid function, activated protein C resistance and the risk of venous thrombosis in users of hormonal contraceptives. Thromb Res. 2014;133(4):640-644.
- Lee JJ et al. Oral contraception and female sexual dysfunction in reproductive women. Sex Med Rev. 2017;5(1):31-44.
- Regidor PA. Clinical relevance in present day hormonal contraception. Horm Mol Biol Clin Investig. 2018;37(1).
- Zimmerman Y et al. The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis. Hum Reprod Update. 2014;20(1):76–105.
- Odlind V et al. Can changes in sex hormone binding globulin predict the risk of venous thromboembolism with combined oral contraceptive pills? Acta Obstet Gynecol Scand. 2002;81(6):482–490.
- Rosen MP et al. A randomized controlled trial of second- versus third generation oral contraceptives in the treatment of acne vulgaris. Am J Obstet Gynecol. 2003;188(5):1158–1160.
- Macut D et al. The influence of combined oral contraceptives containing drospirenone on hypothalamic-pituitary-adrenocortical axis activity and glucocorticoid receptor expression and function in women with polycystic ovary syndrome. Hormones (Athens). 2015;14(1):109-117.
- Diamanti-Kandarakis E et al. A modern medical quandary: polycystic ovary syndrome, insulin resistance, and oral contraceptive pills. J Clin Endocrinol Metab. 2003;88(5):1927–1932.
- Lee CW et al. Oral contraceptive use impairs muscle gains in young women. FASEB J. 2009;23(Suppl 1). Abstract.
- Panzer C 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.