Amenorrhea: Secondary

In amenorrhea, “menorrhea” refers to menstrual bleeding or simply menstruation, while “a” means the absence of something. So, amenorrhea is the absence of menstruation. Now, physiologic amenorrhea is normal and occurs before puberty, during pregnancy and lactation, and after menopause. However, there are also pathologic causes of amenorrhea. Primary amenorrhea refers to situations where a person has never had menstruation by 15 years of age, while secondary amenorrhea occurs when a person who used to have regular menstrual cycles stops having menstruation for at least 3 months.

The menstrual cycle usually lasts about 28 days and starts on the first day of menstruation, when the lining of the uterus begins to shed. The entire process is controlled by the hypothalamic-pituitary-ovarian axis, which is a connection between the hypothalamus, pituitary gland, and ovaries.

First, the hypothalamus releases the gonadotropin-releasing hormone, or GnRH, which travels through blood vessels of the pituitary stalk to reach the pituitary gland. Here, GnRH signals the pituitary gland to release the follicle-stimulating hormone, or FSH, and luteinizing hormone, or LH. Next, FSH and LH travel through the bloodstream to the ovaries where they regulate the release of estrogen and progesterone, which are crucial for maintaining normal menstrual cycles.

Now, secondary amenorrhea covers two scenarios. First, it refers to situations where a person who used to have regular menstruation stops having it for at least three months. Second, it can mean a person who used to have irregular menstruation stops having it for at least six months.

Some of the most important causes of secondary amenorrhea include functional hypothalamic amenorrhea, polycystic ovarian syndrome, hyperprolactinemia, and primary ovarian insufficiency.

First, let’s focus on functional hypothalamic amenorrhea, which occurs under extreme conditions of physical activity or emotional stress.

In individuals who exercise too much, this condition is known as exercise-induced amenorrhea. During prolonged and intense physical activity, the adrenal glands release the stress hormone cortisol, which travels to the hypothalamus and inhibits the release of GnRH. As a result, the body shuts down the hypothalamic-pituitary-ovarian axis, telling ovaries to stop estrogen production, which results in secondary amenorrhea. It’s like the cortisol is saying: “Hey, let’s hold off the next menstrual cycle because there’s no way we can carry the pregnancy in this state.”

Similarly, in extreme emotional stress, the adrenal glands release large amounts of cortisol, shutting down the hypothalamic-pituitary-ovarian axis, stopping the menstrual cycles, and causing secondary amenorrhea.

Functional hypothalamic amenorrhea can also happen with severe weight loss, which is often seen in individuals affected by a restrictive eating disorder, such as anorexia nervosa. Individuals with low body weight have reduced fat stores, and that fat tissue, also known as adipose tissue, is an important source of the hormone leptin. Normally, leptin signals the hypothalamus that the body has enough energy storage to support ovulation and pregnancy. However, with severe caloric restriction and weight loss, there’s hardly any fat tissue, so leptin levels drop. Without leptin, the hypothalamus indirectly gets a message that the body doesn’t have the energy to support a pregnancy, so it shuts down the hypothalamic-pituitary-ovarian axis, which results in secondary amenorrhea.

Diagnosis of functional hypothalamic amenorrhea primarily relies on the history and physical examination, with support from labs, which usually show low levels of GnRH, FSH, LH, and estrogen. Depending on the cause, you might notice low leptin or high cortisol levels. Finally, treatment focuses on restoring energy balance through adequate nutrition and avoiding excessive exercise. Stress reduction and psychotherapy are key as well.

Next up is polycystic ovarian syndrome, or PCOS, which happens because the hypothalamic-pituitary-ovarian axis isn’t working as it should. The exact reason why isn’t fully known, but insulin resistance might be a factor.

In insulin resistance, cells in the liver, muscles, and fat don’t respond well to insulin, so they struggle to absorb glucose. This causes blood glucose levels to rise. As a result, the body signals the pancreas to produce more insulin to bring glucose down. Now, what’s important is that theca cells around the ovarian follicle also have insulin receptors. When insulin stays high, it stimulates theca cells to grow and multiply, and more of these cells means more LH receptors.

At the same time, high insulin levels tell the hypothalamus to release more GnRH, which signals the pituitary gland to pump out more LH. With more theca cells and more LH receptors, LH has a much stronger effect, pushing theca cells to release large amounts of androstenedione. Next, the body converts androstenedione into androgens, like testosterone. As androgen levels rise, they send a signal to the pituitary gland to stop the release of FSH.

Without enough FSH, the follicles can’t grow and mature properly, so the dominant follicle can’t rupture to release the egg. Moreover, the follicle that hasn’t ruptured may either degenerate or remain in the ovary as a cyst. Over time, the ovaries develop a bunch of unruptured follicles or cysts, thus the name polycystic ovarian syndrome.

Ultimately, this LH and FSH imbalance disrupts the menstrual cycle, causing secondary amenorrhea, along with anovulation and infertility.