Amenorrhea: Primary

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 a while.

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, or HPO axis, which is a connection between (you’re never gonna believe this) the hypothalamus, pituitary gland, and ovaries.

First, the hypothalamus releases 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 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, primary amenorrhea covers three scenarios. First, it refers to situations where a person hasn’t had their first menstruation by 15 years of age despite normal growth and the development of secondary sexual characteristics like breasts and pubic hair. Second, it refers to individuals who haven’t had their first menstruation by 13 years of age and haven’t developed secondary sexual characteristics. Third, it can mean no menstruation within five years after breast development begins.

The most important causes of primary amenorrhea include Müllerian agenesis, Turner syndrome, androgen insensitivity syndrome, and imperforate hymen.

Let's start with Müllerian agenesis, also known as Mayer-Rokitansky-Kuster-Hauser syndrome. During early fetal development, all individuals start the development of a reproductive system with a pair of Müllerian ducts.

In biological females, these ducts develop into the uterus, cervix, and the upper two-thirds of the vagina.

However, in biological males, the testes release anti-Müllerian hormone, which causes these ducts to shrink and disappear. In other words, the anti-Müllerian hormone prevents the development of the female reproductive system and promotes the formation of the male reproductive system.

Now, in Müllerian agenesis, “Müllerian” refers to the Müllerian ducts, and “agenesis” means the failure to develop. So, in biological females, the Müllerian ducts fail to develop properly, leaving the uterus, cervix, and upper vagina either missing or severely underdeveloped. And because there’s no uterus, the uterine lining can’t shed, which results in primary amenorrhea. Also, without a uterus, carrying a pregnancy isn’t possible, leading to infertility.

Remember, the ovaries develop independently of the Müllerian ducts, so these individuals have normal production of estrogen and progesterone. As a result, their hypothalamic-pituitary-ovarian axis works normally, so they go through puberty and develop secondary sexual characteristics like anyone else. For diagnosis, order an abdominal ultrasound to identify any structural abnormalities of the reproductive system since surgical treatment is often necessary to address these issues.

Next up is Turner syndrome. Normally, biological females have two X chromosomes and a 46, XX karyotype.

However, in Turner syndrome, they have 45 chromosomes with only one X chromosome present. The second X chromosome could be either partially or completely absent. Either way, one functioning X chromosome is not enough for normal ovarian development, which accelerates the depletion of ovarian follicles.

By age two, the ovaries turn into streak gonads, which are fibrous tissue that cannot produce hormones. So, even though the hypothalamus is releasing GnRH and the pituitary gland is producing FSH and LH, the ovaries are not releasing estrogen or progesterone.

Without estrogen and progesterone, the menstrual cycle never begins, causing primary amenorrhea and infertility.

Also, nonfunctional ovaries can’t trigger puberty, so the body does not develop secondary sexual characteristics. On top of these challenges, individuals with Turner syndrome typically have short stature.

Diagnosis primarily relies on karyotype analysis, which typically reveals the 45, X0 karyotype or, sometimes, 46, XX/45, X0 mosaicism.