There is something these times have uniquely in common – postpartum blues, PMS, the hot flashes and insomnia of menopause… They are marked by low levels of the profoundly important hormone estrogen. There is arguably no greater hormonal shift than the sudden drop of estrogen with the delivery of a baby, hence the surprisingly common incidence of postpartum blues. At a time that should be one of the happiest, a large number of new mothers feel depressed. I have understood the physiology behind postpartum blues and depression, but have wondered how estrogen levels affect us (and my teenage patients) on a day-to-day level. What is the mind-body impact of hormonal fluctuations within our monthly cycles? What oral contraceptives make the most sense for patients seeking cycle regularity, acne treatment and/or cessation of painful periods?

First, let’s analyze the impact of estrogen — Estrogen has a weighty impact on brain function – it has both neuroprotective and neurostimulatory effects. Specifically, estrogen increases the concentration of “feel-good” neurotransmitters (serotonin, dopamine, norepinephrine) in the neuronal synapses, as well as the prevalence of the receptors to which these transmitters bind. Estrogen also increases cerebral blood flow via vessel dilation in the brain and exudes anti-inflammatory effects on cerebral vessels. Inflammatory changes in the brain have been linked to dementia as well as generally reduced cerebral processing. In fact, approximately 80% of perimenopausal women develop mild depressive symptoms beyond the malady that might be attributed to hot flashes, night sweats, and insomnia. These symptoms likely occur because areas of the brain involved in emotion are rich in estrogen receptors and estrogen concentrations directly influence and stabilize serotonin levels. Interestingly, in a medical study involving mice with removed ovaries, administration of estradiol induced a significant increase in serotonin uptake in the frontal cortex and hypothalamus. In fact, among the study mice, the antidepressant imipramine did not exert its therapeutic effect on brain concentrations of serotonin unless estrogen was co-present.

Despite the vast differences between mice and humans, studied women of reproductive age had serum estrogen levels that were positively correlated with higher blood levels of serotonin. Researchers have also demonstrated that blood serotonin is decreased in postmenopausal women and that estrogen replacement therapy raises it to premenopausal levels, with a direct effect on improved mood, memory, sleep and libido. Estrogen also competes with tryptophan, the precursor of serotonin, for binding sites within the body, thus making tryptophan more bioavailable to the brain for conversion to serotonin.

What about estrogen in the form of oral contraceptives (OCPs)? Multiple studies have shown that birth control pills reduce the incidence of endometrial and ovarian cancer, but how do they impact our risk of developing breast cancer? According to some data, if you are one of the few people taking a relatively high estrogen pill, defined as 50mcg or more, you have increased your personal risk of developing breast cancer threefold. Whereas, women taking OCPs that contain a moderate-dose estrogen, 30 to 35 micrograms, potentially increase their odds about 1.5 times, which actually only translates to a 1-2% overall increased risk. Some studies, in fact, argue even this slight increased risk of breast cancer with use of moderate level estrogen containing OCPs. Of note, pills that delivered low-dose estrogen, 20 micrograms or less, did not translate to an increased risk of breast cancer at all.

Because of this data, pharmaceutical companies have been developing OCPs containing lower levels of estrogen. Increased manufacturing of the “Lo” line of pills coupled with mixed data regarding breast cancer risk among traditional pill users, has increased the pool of patients taking low estrogen pills. The clear advantage of the low estrogen pills, aside from the non-effect on breast cancer risk, is that user’s experience a lesser shift during the time of the month where the placebo pills replace the active, hormone pills. This less abrupt drop in estrogen has minimized cramping, mood swings and hormonal headaches among users in the premenstrual period. In addition, these pills tend to contain more “active” pills, so that rather than a week of inactive pills, users only take 2-4 placebo pills, thereby creating shorter, less heavy cycles. Sounds awesome, right? Only, how do you feel during the month? Lower levels of estrogen are tied to depressed mood, less robust cognitive function, poor sleep etc., and if a pill is missed or even taken a few hours off from the previous days dosing time, breakthrough bleeding commonly occurs.

The progestin in an oral contraceptive is also something to consider – the progestin norgestimate is the only one FDA approved for the treatment of acne; the antiandrogenic effects of this pill reduce hormonal breakouts, as well as unwanted hair growth. Norethindrone, like norgestimate, tends to benefit lipid serology (cholesterol levels) in users, whereas some of the newer progestins (levonorgestrel and norgestrel) have been shown to raise LDL and lower HDL (the good cholesterol). Desogestrel has been touted as a well-tolerated progestin except some clinical trials indicated an increased incidence of non-fatal blood clots in patients who took this medication. Drospirenone, trade name Yaz, has been FDA approved to help with PMS, but does effect serum potassium levels and thus must be used with caution, especially among patients with kidney disease. Of note, there was a slight increased breast cancer risk demonstrated among pills that contained a type of progestin called ethynodiol diacetate, as well as among triphasic pills containing the progestin norethindrone (Estrostep).

Through the research conducted on this subject, it makes sense to me to use medium estrogen containing pills – 25mcg – 30mcg for most patients, specifically ones that contain the progestin norgestimate, as it has been clearly shown to improve hormonal acne and has a positive effect on lipid levels. If a patient smokes or has a family history of clotting disorders, a pill of any kind is not the appropriate choice. Some teenagers and adults will certainly benefit from a very low estrogen containing pill, for the reasons outlined above, but the minimal estrogen content of these pills has real potential negative effects on overall well-being. In the end, it may take trying a few different types of pills to determine which works the best for you or your teenage daughter, but if you don’t respond well to a low estrogen pill (despite the pharmaceutical push) there is a real physiologic reason why.

 

References:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1327664/ (BMC Womens Health. 2005; 5: 12.

Published online Dec 20, 2005. doi:  10.1186/1472-6874-5-12 PMCID: PMC1327664

An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology

Leszek A Rybaczyk, Meredith J Bashaw,Dorothy R Pathak,Scott M Moody,Roger M Gilders, and Donald L Holzschu)

http://www.fhcrc.org/en/news/center-news/2014/08/Some-new-birth-control-raise-breast-cancer-risk.html

http://www.cancer.gov/cancertopics/factsheet/Risk/oral-contraceptives

http://www.nejm.org/doi/full/10.1056/NEJMoa013202#t=articleResults

http://www.medscape.com/viewarticle/406718_2 (Journal of the American Pharmacists Association Effects of Estrogen on Cognition, Mood, and Degenerative Brain Diseases, Janet E. Shepherd; Journal Am Pharm Assoc. 2001;41(2) )

“Types of Progestin Found in Combination Birth Control Pills” By Dawn Stacey M.Ed, LMHC, Contraception Expert