Examining the Evidence
Q. Does the dosage of estradiol in OCs affect mood and sexual interest?
<huc>A.</huc> It may affect premenstrual mood. In this comparison of two oral contraceptives (OCs) containing the same progestin but different dosages of ethinyl estradiol, women using the 25-μg formulation were significantly more likely to report improvement in premenstrual mood than were those using the 35-μg pill, although this effect was not reflected in measures of free testosterone (FT) or dehydroepiandrosterone sulfate (DHEA-S). Sexual interest was not affected significantly with either formulation.
The progestin used in this study was a triphasic regimen of norgestimate in dosages of 0.18, 0.215, and 0.25 mg.
OCs are the most widely used method of reversible contraception in the world.1 Since the 1970s, at least 50% of users have reported emotional lability, depression, magnification of premenstrual symptoms, and decreased libido2-4—and almost 30% have cited these effects as a reason for discontinuing the pill.5 As Greco and colleagues point out, complaints of depression and decreased libido have diminished somewhat since lower-dose (<35 μg) ethinyl estradiol formulations were developed. The psychopharmacology underlying these symptoms, and whether the decreased libido and mood changes share a common etiology, have yet to be clarified.
There are many potential reasons for the emotional lability, increased premenstrual symptoms, and decreased libido associated with OCs, including:
- abrupt withdrawal of hormones in regimens containing 21 active pills followed by a 7-day pill-free interval
- suppression of endogenous hormones, including biologically available testosterone, dehydroepiandrosterone, and other neuroactive steroid metabolites of progesterone
- direct adverse effects of the estrogen or progestin
- genetic and environmentally determined “vulnerability factors.”
Strengths of the study
By comparing two triphasic OCs with identical progestin dosages but different quantities of ethinyl estradiol, the authors isolated the variable of estrogen dose. They also assessed concentrations of FT and DHEA-S, and measured depression and sexual interest using reliable tools.
Another strength is that women were prospectively randomized to the two regimens and studied during the first 3 months of OC use—before discontinuation due to side effects, although there were some study dropouts.
Effects on hormones, mood
As expected, the lower-dose OC reduced FT to a lesser degree than did the 35-μg pill. Overall, scores on the Beck Depression Inventory during the premenstrual week showed a slight improvement in mood in both groups after 3 months on the OC. However, a greater percentage of women using the 25-μg formulation showed improvement in mood, although the authors were careful to point out that a causal relationship between this improvement and the dosage of estradiol cannot be confirmed.
The authors also noted that improvement in premenstrual mood with OC use has previously been reported, but wrongly claimed that placebo-controlled studies have not shown a significant difference between OC and placebo for this variable. On the contrary, I would point to two recent randomized trials that demonstrated efficacy of an OC containing 20 μg of ethinyl estradiol and 3 mg of the progestin drospirenone in a 24/4-day regimen for the severe form of premenstrual syndrome called premenstrual dysphoric disorder (PMDD).6,7 This formulation received Food and Drug Administration approval for treatment of PMDD in women who desire hormonal contraception.
The mildly anti-androgenic drospirenone, a spironolactone analogue equivalent to approximately 25 mg of spironolactone, has not been studied in isolation (ie, apart from a combination OC) with respect to premenstrual mood and sexual functioning. However, its anti-androgenic effect was not deleterious in the PMDD studies6,7 and may have played a role in treatment outcome—although a similar study of the same dose of drospirenone combined with 30 μg of ethinyl estradiol in a 21/7-day regimen was not more effective than placebo for severe premenstrual symptoms.8 One reason may be that the 24/4-day regimen provides more complete suppression of the hypothalamic–pituitary–ovarian axis.
DHEA-S and other neuroactive steroid metabolites of progesterone are suppressed in women taking OCs. One study found no deterioration in mood despite suppression of these steroids in women given a 20-μg OC.9 Paoletti and associates10 have even suggested that the suppression of DHEA-S may be responsible for mood improvement with the OC containing 30 μg of ethinyl estradiol and 3 mg of drospirenone, compared with untreated women.
Symptoms were assessed only during premenstrual week. Because the women in the study by Greco and colleagues did not complete daily mood ratings, it is impossible to know whether the OC with the lower dose of ethinyl estradiol was better for moodiness unrelated to the premenstrum. Other symptoms of premenstrual syndrome, such as anxiety, irritability, and mood swings, were not assessed prospectively.
Bottom line: Lower dose of estradiol is probably better
The study by Greco and colleagues adds to evidence that an OC containing a lower dose of ethinyl estradiol is better for premenstrual mood, although this effect is unlikely to be related to its effect on androgens. It remains unclear how a lower estrogen dose affects mood in women who have a history of premenstrual syndrome and whether mood improvement with a lower estrogen dose is related to a lower degree of androgen suppression.
When there is concern about a patient’s mood or depression, prescribe a low-dose OC, such as one containing 20 μg of ethinyl estradiol and 3 mg of drospirenone in a 24/4-day regimen (Yaz). Most women experience no adverse effects of OCs on mood. Those with a history of depression should be aware that there may be a deterioration of mood on the OC.
1. Sulak PJ, Kuehl TJ, Ortiz M, Shull BL. Acceptance of altering the standard 21-day/7-day oral contraceptive regimen to delay menses and reduce hormone withdrawal symptoms. Am J Obstet Gynecol. 2002;186:1142-1149.
2. Kurshan N, Epperson CN. Oral contraceptives and mood in women with and without premenstrual dysphoria: a theoretical model. Arch Womens Ment Health. 2005;9:1-14.
3. Oinonen KA, Mazmanian D. To what extent do oral contraceptives influence mood and affect? J Affect Disord. 2002;70:229-240.
4. Sanders SA, Graham CA, Bass JL, Bancroft J. A prospective study of the effects of oral contraceptives on sexuality and well-being and their relationship to discontinuation. Contraception. 2001;64:51-58.
5. Goldzieher JW. Are low-dose oral contraceptives safer and better? Am J Obstet Gynecol. 1994;171:587-590.
6. Yonkers KA, Brown C, Pearlstein TB, Foegh M, Sampson-Landers C, Rapkin A. Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder. Obstet Gynecol. 2005;106:492-501.
7. 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.
8. Freeman EW, Kroik R, Rapkin A, et al. Evaluation of a unique oral contraceptive in the treatment of premenstrual dysphoric disorder. J Womens Health Gend Based Med. 2001;10:561-570.
9. Rapkin A, Morgan M, Sogliano C, Biggio G, Concas A. Decreased neuroactive steroids induced by combined oral contraceptive pills are not associated with mood changes. Fertil Steril. 2006;85:1371-1378.
10. Paoletti AM, Lello S, Fratta S, et al. Psychological effect of the oral contraceptive formulation containing 3 mg of drospirenone plus 30 μg of ethinyl estradiol. Fertil Steril. 2004;81:645-651.