Here’s the basic biology of sex: Women are born with a pair of X chromosomes. Women are also usually born with an abundance of a hormone or chemical messenger called estrogen. Men are born with an X and a Y chromosome and usually an abundance of androgens or steroid hormones, the major one being testosterone.

Most of us learned these facts in biology class. But we didn’t need a book to see those hormones in action. They were expressing themselves all around us in the years-long process that is puberty.

Puberty is a time of hormonal fluctuations that start around 11 for most girls and 12 for boys. These fluctuations affect behavior and change your body’s form well beyond pubic hair. Females grow breasts and start their periods as their ovaries, vagina, and uterus mature. Males become muscular, develop a lowered voice, start growing hair all over their body, and as any parent of a teen[1]age boy knows, start stinking up every room in the home from their oily skin and sweat. All of this is basic stuff.

What may not be obvious is that most autoimmune diseases begin at puberty and that women are at higher risk of getting these diseases right after puberty. What is not clear is how and why the emergence of these sex differences take on a new role in the immune system at the time of puberty.

Sex hormones do have a role in making autoimmune and other diseases better or worse, promoting or inhibiting immune functions, but they cannot explain their causes. It is curious and confounding.

Henry G. Kunkel, my mentor and a renowned immunologist at Rockefeller University, was the first to clue me in to the role sex differences has on your immune system, including the fact that autoimmune diseases are more common to women than men. My own research on autoimmune diseases has shown this as well. For example, I have spent decades studying lupus (a disease that is very classically autoimmune and can destroy almost every system of the body), and there are no fewer than ten times as many women affected with the disease than men.

There are many more of these diseases, many of which are not as widely known and some of which we touched on in this book including primary biliary cirrhosis (a terrible disease that attacks the liver), Sjogren’s syndrome (in which the glands of the body are inflamed and the patient has little saliva or tears), and of course the most common autoimmune disease, rheumatoid arthritis (in which joints are destroyed and patients have to endure tremendous amounts of pain and immobility throughout their lives).

The question is: What role might hormones like estrogen play in these diseases? The answer eludes us, and some of the observations about what role sex differences play have been baffling.

A few years after the advent of the first oral contraceptive in the 1960s—which contained estrogen and progestin, a synthetic form of the progesterone hormone to prevent ovulation—physicians asked whether the advent of the “pill” had any major effects on rheumatoid arthritis manifestations. After all, it was found that some women who had rheumatoid arthritis tended to improve during certain times during menstruation when estrogens were the highest.

In clinics, doctors would ask women about their symptoms and try to pair them with phases of their menstrual cycles. No surprise! Symptoms of rheumatoid arthritis like pain and fatigue were far worse right before the onset of the period. When the bleeding began, the symptoms abated. But in multiple clinical trials with women on and off oral contraceptives there was no measurable effect on the course of rheumatoid arthritis.

And with lupus, many observations revealed the reverse: Symptoms would get worse right before the onset of the menstrual period and then improve with the onset of the period. In other words, symptoms varied by both disease state as well as from woman to woman.

The only consistency was that the vast majority of patients could predict exactly how they would feel when their periods would start and end based on their symptoms, which led me and many others to believe estrogen played a major role in modulation of disease activity.