Premature ovarian failure

In premature ovarian failure, which is also called primary ovarian insufficiency, the ovaries stop functioning normally, and this means that they stop ovulating, or releasing egg cells, and they also stop producing hormones, mainly estrogen and progesterone, and this all happens before a woman is 40 years old. It’s considered a “primary” problem because the problem is with the ovaries themselves, rather than glands or hormones that act on the ovaries.

Normally, the hypothalamus, which is located at the base of the brain, secretes gonadotropin-releasing hormone, or GnRH. GnRH makes the nearby pituitary gland secrete two hormones of its own, called gonadotropins. These are follicle stimulating hormone, or FSH, and luteinizing hormone, or LH. These hormones travel to the follicles within the ovaries. The follicles are small clusters of granulosa and theca cells that protect the developing egg cell.

FSH acts on the granulosa cells, making the follicles grow and mature, as well as secrete estrogen, while LH stimulates theca cells to secrete progesterone and small amounts of androstenedione, which is a precursor of testosterone. All three of these hormones belong to a class of steroids, or lipid-soluble hormones.

At birth, a woman has millions of follicles, each ready and excited to do its job. During puberty, the monthly menstrual and ovarian cycles begin, which is when the endometrium, or inner lining of the uterus, goes through cyclic changes in response to the ovarian hormones.

During the ovarian cycle, the ovarian hormones also help a handful of follicles to start growing. Eventually, there’s ovulation which is when a single follicle fully matures and ruptures, releasing its egg cell, while the other follicles degenerate and die off.

Over time, many ovarian follicles degenerate, and the ones that remain become less and less sensitive to gonadotropin stimulation. This goes on until menopause, when there are no remaining follicles responding to gonadotropins, and that causes menstruation and ovulation to cease entirely. In most women, this occurs between the ages of 40 and 60.

Now, in premature ovarian failure, the follicles stop responding to gonadotropin stimulation earlier than usual - that being before the age of 40. In the majority of cases, there’s no clear cause. In some cases, it’s linked to chromosomal abnormalities like Turner syndrome, where an X chromosome is missing. Other times it can be a gene mutations, like BRCA1, or in a syndrome like Fragile X syndrome, which is caused by the expansion of a trinucleotide repeat within a gene on the X chromosome. In other cases, the ovaries can get harmed by chemo- or radiotherapy, or by autoimmune destruction, where the immune system goes rogue and attacks the ovaries.

There are two proposed mechanisms that could explain how premature ovarian failure develops. The first mechanism is that there are few or no remaining follicles in the ovary, and this could be because the ovary started out with only a few or because a lot of them degenerated too quickly.

The second mechanism is that the follicles are dysfunctional, meaning that they’re present but simply can’t do their normal job. Either because they can’t generate gonadotropins themselves or because they don’t respond to the gonadotropins, or because they can’t generate hormones themselves.