By Jeffrey T. Jensen, MD, MPH

Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland

Dr. Jensen reports that he is a consultant for and receives grant/research support from Bayer, Abbvie, ContraMed, and Merck; receives grant/research support from Medicines 360, Agile, and Teva; and is a consultant for MicroChips and Evofem.

SYNOPSIS: Users of the levonorgestrel (LNG) intrauterine system showed an exaggerated response to stress compared to women using a combined LNG pill or those with natural cycles.

SOURCE: Aleknaviciute J, Tulen JHM, De Rijke YB, et al. The levonorgestrel-releasing intrauterine device potentiates stress reactivity. Psychoneuroendocrinology 2017;80:39-45.

Although side effects due to hormonal contraception receive little attention from clinicians in the United States, the topic remains front and center in the minds of European women and medical experts. Lacking from the debate on whether hormonal contraception causes an adverse effect on mood have been sound mechanistic arguments demonstrating how the effect might be mediated. Aleknaviciute et al conducted two experimental studies and one cross-sectional study in Rotterdam, Netherlands, to explore this question. For all three studies, they compared naturally cycling (NC) women to groups using the 20 µg/d levonorgestrel intrauterine system (LNG IUS) or a combined oral contraceptive (COC) containing ethinyl estradiol (30 µg) and levonorgestrel 150 µg. The authors recruited healthy, non-obese women (18 to 45 years old) through posted flyers and local internet advertisements, and financially compensated them for their participation. To be eligible, women in the hormonal contraceptive groups needed to report use of the method for at least four months, while those in the NC group could not have used a hormonal method for the same time interval. They further screened potential subjects using a clinician-administered Structured Clinical Interview for DSM-IV Axis I disorders, and excluded women with any Axis I psychiatric disorder (acute or in remission), current pregnancy or lactation, thyroid disorder, recent (within four months) medical illness, or use of any prescription medication other than hormonal contraceptives. They also excluded women with a prior diagnosis of endometriosis, polycystic ovary disease, or gynecologic infection, and those using hormonal contraceptives for treatment or prophylaxis of gynecological (e.g., heavy menstrual bleeding) or dermatological (e.g., acne) conditions. To reduce variability in assessment, the investigators tested subjects in the NC group during the luteal phase and those in the COC group during the active pill weeks. They tested women using the LNG IUS with a regular cycle during the luteal phase. The LNG IUS subjects with amenorrhea (proportion not described) were tested at an unknown time in the cycle.

In Study 1, the authors measured salivary cortisol at baseline and at defined intervals following the Trier Social Stress Test (TSST; LNG IUS, n = 15; COC, n = 15; NC, n = 25). The TSST involves a preparation period, free speech task, and verbal mental arithmetic task (each five minutes in duration), with continuous heart rate monitoring throughout the test. Compared to women with NC (10.85 ± 11.03 nmol/L) and those using COC (3.27 ± 2.83 nmol/L), users of the LNG IUS had an exaggerated salivary cortisol response to the TSST (24.95 ± 13.45 nmol/L; P < 0.0001). LNG IUS users also showed a significantly potentiated increase in heart rate during the test. To explore the possibility that the effect was due to the presence of an intrauterine device and unrelated to LNG, the investigators enrolled an additional 10 women using a copper IUD and performed the TSST. The results from this group were similar to the NC controls.

For Study 2, the team performed a low-dose (1 µg) adrenocorticotropic hormone stimulation test, and obtained salivary cortisol as well as serum total cortisol and serum cortisol-binding globulin (LNG IUS, n = 20; COC, n = 20; NC, n = 20). In this study, the COC group displayed a significantly higher total serum cortisol response in comparison with the NC or LNG IUS groups. However, this effect disappeared after adjusting for corticosteroid-binding globulin (known to increase with COC use).

Study 3 evaluated “naturalistic cortisol exposure” in 95 women (LNG IUS, n = 33; COC, n = 33; NC, n = 29). For this experiment, the investigators removed approximately 150 hairs as close to the scalp as possible from the posterior vertex of the scalp. They then used the most proximal 3 cm of the sample to extract cortisol values for comparison; they found that LNG IUS users had significantly elevated levels of hair cortisol compared to the COC and NC groups.

Taking these results together, the authors concluded that, compared to women using a COC containing LNG or those experiencing natural cycles, use of the LNG IUS induces a centrally mediated sensitization of both autonomic and hypothalamic-pituitary-adrenal axis responsivity, indicating an altered systemic physiological response to stress.

COMMENTARY

Does this study provide evidence of a mechanism to support a link between hormonal contraception and depression? As you recall, Skovlund et al used the Danish National Database to evaluate this question, and found generally weak associations (risk elevations under 2.0) for hormonal contraception use and incident diagnosis of and treatment for depression.1 In my comments last year, I discussed the weaknesses of the Skovlund study, including the failure to capture baseline confounders, the weak associations, and the absence of a dose-response for progestin-only methods.2

More recently, Zethraeus et al published results of a double-blind, placebo-controlled randomized trial of 340 women in Sweden, and demonstrated a statistically significant decrease in general well-being among women receiving the active COC (30/150 EE/LNG) compared with placebo, but no effect on depressive symptoms or depressed mood.3 In a second double-blind, randomized, controlled trial from Sweden also published this year, women who received active treatment with the non-androgenic progestin nomegestrol acetate in combination with estradiol reported significantly more mood side effects than women randomized to placebo.4 However, the proportion of women in this study with clinically relevant mood worsening did not differ between the COC and placebo groups. Of greater importance, secondary analyses showed that women with previous adverse hormonal contraceptive experience reported significantly greater mood worsening in the intermenstrual phase in comparison with healthy women, suggesting that a susceptible phenotype may exist. Limitations of both of these studies included the short interval of study (3 to 4 months), as known COC-related treatment-emergent adverse systemic side effects (such as breakthrough bleeding, acne, breast tenderness) that tend to decrease over time may have influenced the outcomes. Older studies have demonstrated improvement in mood associated with continuous use of LNG COCs5 and with a reduced hormone-free interval in a drospirenone COC.6 These results align with the null effect on stress response of the LNG COC users in the Aleknaviciute study.

How might a progestin-only method that does not affect cyclicity, such as the LNG IUS, influence stress response and mood? And if progestins have a negative effect, why does the addition of an estrogen result in improvement? Some investigators hypothesize that progestin treatment decreases levels of the progesterone metabolite and potent GABAA receptor agonist allopregnanolone in the brain.7,8 Although progestin-only methods that block ovulation, such as the implant, injection, or desogestrel pill, certainly prevent luteal levels of progesterone, most LNG IUS users ovulate after the initial months of use, so this mechanism does not explain the findings reported by Aleknaviciute.

We must consider several important limitations of the Aleknaviciute study before accepting that the LNG IUS results in an altered response to stress. First, self-selection of method results in considerable opportunity for bias. Although the authors attempted to screen out women using a hormonal method for a non-contraceptive benefit, important differences may have influenced choice. In particular, women with concerns regarding hormone effects on mood may have been more likely to use an LNG IUS. LNG IUS users reported much shorter durations of use of the method. This suggests that common but transient treatment-emergent side effects seen with initiation of a hormonal method (particularly the great increase in unscheduled bleeding seen with early use of the LNG IUS) might have influenced the results. Given the importance of contraception to women’s lives, and proven efficacy benefit of long-acting reversible contraception methods, we must carefully evaluate any possible association for concern. A true prospective study that sorts out these effects would be a major contribution to the literature.

To respond to the Aleknaviciute and Skovlund studies, the European Society for Contraception (ESC) published a consensus expert statement on the effects of progestin-only contraceptives and mood,9 raising many of the issues discussed in this commentary. This makes good reading for those who want more information on this issue. I am surprised that this controversy has not made headlines in the United States, given the widespread acceptance and push for greater use of long-acting reversible contraception methods. But perhaps we are distracted by other issues. The ESC recommends a patient-centered approach that emphasizes identifying women who may be at risk for adverse mood changes by taking a thorough history, discussing the possibility of adverse mood effects, and recommending a follow-up visit to discuss options in situations where troublesome adverse effects present. This sounds like good advice for clinical practice while the science settles.

REFERENCES

  1. Skovlund CW, Morch LS, Kessing LV, Lidegaard O. Association of hormonal contraception with depression. JAMA Psychiatry 2016;73:1154-1162.
  2. Jensen JT. Hormonal contraception: A risk factor for depression? OB/GYN Clin Alert 2016;33:57-59.
  3. Zethraeus N, Dreber A, Ranehill E, et al. A first-choice combined oral contraceptive influences general well-being in healthy women: A double-blind, randomized, placebo-controlled trial. Fertil Steril 2017;107:1238-1245.
  4. Lundin C, Danielsson KG, Bixo M, et al. Combined oral contraceptive use is associated with both improvement and worsening of mood in the different phases of the treatment cycle — A double-blind, placebo-controlled randomized trial. Psychoneuroendocrinology 2017;76:135-143.
  5. Halbreich U, Freeman EW, Rapkin AJ, et al. Continuous oral levonorgestrel/ethinyl estradiol for treating premenstrual dysphoric disorder. Contraception 2012;85:19-27.
  6. Pearlstein TB, Bachmann GA, Zacur HA, Yonkers KA. Treatment of premenstrual dysphoric disorder with a new drospirenone-containing oral contraceptive formulation. Contraception 2005;72:414-421.
  7. Moller AT, Backstrom T, Nyberg S, et al. Women with PTSD have a changed sensitivity to GABA-A receptor active substances. Psychopharmacology (Berl) 2016;233:2025-2033.
  8. Amin Z, Mason GF, Cavus I, et al. The interaction of neuroactive steroids and GABA in the development of neuropsychiatric disorders in women. Pharmacol Biochem Behav 2006;84:635-643.
  9. Merki-Feld GS, Apter D, Bartfai G, et al. ESC expert statement on the effects on mood of the natural cycle and progestin-only contraceptives. Eur J Contracept Reprod Health Care 2017:1-3.