Drugs and Sex: Educating Yourself About Treating Women
Originally published in Psychopharmacology Update 13(3):1,4, 2002.
Introduction
According to Laura J. Miller, M.D., associate professor of psychiatry and chief of the Women's Services Division at the University of Illinois at Chicago, women take more psychotropic medications than men, and yet, until recently, most pharmacologic research was conducted on men.
At the 14th Annual U.S. Psychiatric and Mental Health Congress in Boston, Miller talked about important gender and sex differences and reviewed the following key points that can inform optimal prescribing practice.
Gender differences may affect patterns of use and reactions to medications in several ways, including the way medications get to and from their site of action—their pharmacokinetics. The way the medication is absorbed in the GI tract, the way it is distributed through the body up until the brain, and the way it is metabolized out of the body can differ in males and females. Doses quoted according to typical male body size may be too strong for the average woman. Reproductive cycle events affect the potential risk factors and ways a woman's body handles medications. Things like menstruation, pregnancy, postpartum and menopause, exogenous hormones that she takes for conception or fertility or menopausal symptoms—all this can interact with pharmacologic agents.
"Weight gain is a side effect that is equally common in men and women, but feeling bad about weight gain and having weight gain be a reason to discontinue a drug, or not try a drug, is far more common in women, as compared to men," said Miller.
Among the things that are not quite so obvious is stomach acidity. A woman's stomach is more basic, less acidic, than a man's, and this means differences in how women absorb different drugs. Drugs that are weak acids, like valproic acid (Depakote), are less well absorbed in this environment. Drugs that are weak bases, like most antidepressants, are better absorbed in this less acidic environment.
"Female GI tracts are slower than those of males," said Miller. "The intestine may be slowed in women compared to men, which means that whatever got past the stomach has more time to get absorbed. So, you can't assume that a woman is absorbing a drug the same way as a man, sometimes there are significant differences."
Effects on Fertility
Psychopharmacologic agents have a number of effects on fertility—effects that can go in both directions. Medications can increase fertility and when they do, it is usually because of their effect on the symptoms of the disease they are treating. In the case of depression, once the depression is lifted, the person may have increased sexual desire, increased interest in relationships, and therefore be more likely to conceive a baby. The same can be true with agents that help with negative symptoms of schizophrenia; the ability to have intimate relationships is enhanced.
Decreases in fertility are usually biologically based, or a direct side effect of medication. For example, sexual dysfunction or lack of sexual interest is a common medication side effect. Hyperprolactinemia is a common side effect of some antipsychotic medications. Polycystic ovary syndrome (POS) has been associated with use of valproate in young women. All of these can impair fertility.
Menopause
Some women who have been on a steady dose of a medication find they need a dosage adjustment as they enter menopause, as some of the sex differences that existed pharmacokinetically before menopause decrease or disappear at this time.
The most prominent pharmacokinetic sex difference that changes at this age is gastric emptying time, which until now had been slower for women. Cerebral blood flow, which had been greater for women than men during the reproductive years, also will change as women experience menopause.
Exogenous Hormones
Taking exogenous hormones, such as the commonly used oral contraceptives (OC), magnifies preexisting sex differences in pharmacokinetics and makes them more extreme. OC effectiveness can be reduced by medications that induce hepatic enzymes that metabolize them. Carbamazepine (Tegretol), for example, is a strong inducer of the same enzymes that would metabolize OC.
OC can contribute to depressed mood and work against antidepressant medication. If a woman is not responding to an antidepressant, consider the OC as a contributory factor.
"This was seen more often in the days when there were much higher doses of hormones in OC but there still are women who even at low dose OC are sensitive to their depressogenic effects, so when you do find that, you can either switch to an OC with a different formulation, or you can use a different form of contraception altogether," said Miller.
Some women's OC depressions are pyridoxine (vitamin B6) sensitive and if they supplement with pyridoxine they no longer have the problem. For others, adequate doses of antidepressant medication will override the contributory factor of the OC.
Exogenous hormones also come into play at menopause, when women begin taking hormone replacement therapy (HRT).
"These are natural estrogens as opposed to the synthetic estrogens in OC and so they don't affect hepatic enzyme induction as much. They do maintain the sex differences in gastric acid secretion, so pharmacokinetically speaking, a woman on hormone replacement therapy is similar to a woman in her reproductive years."
HRT can directly affect mood as well. In getting used to estrogen initially, a woman may be irritable, tense or anxious for a period. Later on, long-term estrogen has sort of a mild, anxiolytic effect instead.
"Several strategies can be tried for women who have mood-related side effects on HRT, such as changing from a cyclic one to a continuous one where the estrogen and progesterone are given simultaneously," said Miller. "Or, you can try lowering the dose of progesterone or giving a different type of it. If that doesn't work you can skip some months and use progesterone every other or every third month if absolutely necessary."
Estrogen as Pharmacotherapy
"Estrogen has some effective uses as a psychotropic agent, at least in early studies, but it's not something that we have enough data about to be using in a widespread manner," said Miller.
Preliminary studies show efficacy for postpartum depression for estrogen. It has been used transdermally as a patch and it has been used sublingually, and been shown effective in both of those forms. It has also been shown effective as an oral capsule for preventing postpartum depression in high-risk women, where the initial dose was high, then gradually tapered down so it would be a less abrupt drop of estrogen postpartum.
It has also been used as an effective adjunct to an antidepressant for perimenopausal women.
Estrogen can trigger mania in women with bipolar diatheses, so it is important to check for bipolar family history or personal history of hypomania if you intend to use estrogen.
"We don't have any studies going head to head, estrogen versus an antidepressant, and there are a number of contraindications—hypercoagulability, breast cancer or any risk factors for breast cancer and pregnancy being the major ones," said Miller. "Long term use of unopposed estrogen can increase endometrial cancer risk, but adding progesterone can cause depression to come back, so that doesn't help."
The most important thing to remember when considering estrogen as a psychotropic agent is that its efficacy and safety relative to conventional agents has not been established.
Conclusion
Miller suggests some general principles to provide optimal pharmacotherapy treatment for women:
Adjust your starting doses for the weight of the woman and pharmacokinetic differences—i.e., sometimes start at a lower dose than you otherwise would.
Ask whether her symptoms, side effects or drug concentrations change across her menstrual cycle.
Ask about any exogenous hormones, including herbal hormone substitutes, she is taking or considering taking.
When primary pharmacotherapeutic interventions are not working, consider hormonal therapies.
Discuss any potential risks that medications may have during pregnancy and nursing for all women of reproductive age.
