Amenorrhea

Definitions & Key takeaways

Amenorrhea is the absence of menstrual periods in women during reproductive years. There are two types of amenorrhea: primary and secondary. Primary amenorrhea is when periods have never started by the time a girl reaches 16 years old. Secondary amenorrhea is when periods have stopped for at least three months, even if they had started in the past.

There are many possible causes of amenorrhea, including pregnancy, hormone problems, problems with the ovaries or uterus, eating disorders, excessive exercise, and stress.

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Introduction0:00–0:26

Amenorrhea means no menstruation. It’s normal before puberty, during pregnancy and lactation, and after menopause.
Sometimes though, menstruation either never starts, which is called primary amenorrhea, or suddenly stops in a person who’s previously menstruating, which is called secondary amenorrhea.
Now, menstruation, and the menstrual cycle as a whole are controlled by the hypothalamus and the pituitary gland, all the way up in the brain.

Physiology0:26–2:35

The hypothalamus secretes gonadotropin-releasing hormone, or GnRH, which makes the nearby anterior pituitary gland release follicle-stimulating hormone, or FSH, and luteinizing hormone, or LH.
In the first two weeks of an average 28-day cycle, the ovaries go through the follicular phase, meaning that out of the many follicles scattered throughout the ovaries, a couple of them enter a race to become the dominant follicle, that will be released at ovulation.
All the developing follicles secrete loads of estrogen, which negatively inhibits pituitary FSH. In the meantime, the uterus goes through two phases: the menstrual and proliferative phase.
During the menstrual phase, the functional layer of the endometrium is shed and eliminated through the vagina, leading to menstruation, which lasts an average of five days.
It’s followed by the proliferative phase, during which the rising levels of ovarian estrogen make the functional layer of the endometrium thicken and sprout endometrial glands.
Additionally, spiral arteries emerge to nourish the growing functional endometrium. After ovulation, the ovaries enter the luteal phase, which lasts for the two weeks following ovulation.
During the luteal phase, the remnant of the ovarian follicle, called the corpus luteum, makes progesterone, which negatively inhibits pituitary LH.
Progesterone makes the endometrium go through the secretory phase, during which it thickens some more, and spiral arteries continue to grow.
If the egg is not fertilized by a sperm, estrogen and progesterone levels slowly decrease. When progesterone reaches its lowest level, the spiral arteries collapse, and the functional layer dies off and is eliminated through menstruation, which marks the beginning of a new menstrual cycle.

Primary amenorrhea pathology2:35–5:49

Ok, now, coming back to amenorrhea. Primary amenorrhea is when a female hasn’t had her first menstruation, called menarche, by age 16, despite normal growth and having started puberty.
Primary amenorrhea is also suspected when a female hasn’t had menarche by age 13 and doesn’t show signs of puberty, which include developing secondary sexual characteristics like breasts.
The most common cause of primary amenorrhea is Turner syndrome, where one X chromosome is either completely or partially absent.
The most common karyotype is 45, X, which means the person has 45 chromosomes, of which only one is an X chromosome. With Turner syndrome, the ovaries are replaced by streak gonads, or functionless, fibrous tissue.
This happens because the missing X chromosome leads to accelerated ovarian follicle depletion, so that by two years old, none are left, essentially causing “menopause before menarche”.
No ovarian follicles also means no estrogen and progesterone, which leads to high levels of FSH and LH. The second most common cause of primary amenorrhea is Müllerian agenesis, which is also called Mayer-Rokitansky-Kuster-Hauser syndrome.
In this case, the Müllerian duct system doesn’t develop properly in a biologically female fetus. The Müllerian duct system is responsible for the development of the uterus, cervix and upper two thirds of the vagina, so these organs may be absent, or rudimentary and obstructed, which explains the absence of menses.
But the ovaries develop normally in these individuals, and the ovarian follicles make normal amounts of estrogen and progesterone, so there are normal levels of FSH and LH.
A rarer cause of primary amenorrhea is androgen insensitivity syndrome. In this case, the individual is biologically male, which means they have a 46, XY karyotype, but their androgen receptors don’t respond to testosterone.
So they don’t have an uterus, fallopian tubes or ovaries, which explains the absence of menses. But they have testicles, which are usually in the abdomen or the inguinal canal, and they make the normal amount of testosterone for a biologically male individual, so FSH and LH levels are normal.
Some of that testosterone gets converted to estrogen, so these people have female external genitalia and female secondary sex characteristics.
Finally, endocrine disorders can also cause primary amenorrhea. These include Kallmann syndrome, where GnRH producing neurons fail to migrate from the nose region to the hypothalamus during fetal development.
This causes low levels of GnRH, FSH, and LH, and, as a consequence, low estrogen, so puberty either never starts or is incomplete.

Secondary amenorrhea pathology5:49–9:18

Ok, now let’s switch gears at look at causes of secondary amenorrhea, which is defined as no menstrual bleeding for at least three normal menstrual cycles in a female who previously had regular cycles, or for six months for females who used to have irregular cycles.
There are many causes of secondary amenorrhea, and when they occur before menarche, all of these can also cause primary amenorrhea.
The most common cause of secondary amenorrhea is pregnancy. Next, there’s functional hypothalamic amenorrhea, which is when there is a decrease in GnRH secretion, leading to low levels of LH, FSH, and estrogen.
Often, this is due to weight loss from anorexia, nutritional deficiencies like excessively low fat consumption, prolonged periods of strenuous exercise, or severe physical or emotional stress.
Another condition that affects the hypothalamic-pituitary-ovarian axis and can be responsible for secondary amenorrhea is polycystic ovary syndrome.
Now, it’s not clear exactly what causes PCOS, but there seems to be an imbalance between LH and FSH levels. Specifically, ovulation doesn’t occur, so progesterone levels don’t rise enough to inhibit LH production.
This leads to an increase in the production of LH compared to FSH, so there’s an elevated LH to FSH ratio. Additionally, because there is post-ovulatory rise and fall in progesterone, there is no menstruation.
Issues with the pituitary gland can also cause secondary amenorrhea. One cause is hyperprolactinemia, or excessive prolactin secretion by pituitary lactotroph cells, which is frequently seen with a benign pituitary tumor called a prolactinoma.
High prolactin levels inhibit hypothalamic GnRH production, therefore inhibiting ovulation and menstruation. Interestingly, hypothyroidism - a condition in which there’s low levels of thyroid hormones - can also cause amenorrhea.
This is because low thyroid hormone levels tell the hypothalamus to release more thyrotropin-releasing hormone, or TRH, and tell the pituitary to release more thyroid stimulating hormone, or TSH.
When this happens, TRH also stimulates prolactin release - so hyperprolactinemia and amenorrhea occur. Now, sometimes secondary amenorrhea can occur because of premature ovarian failure - which is when the ovarian follicles undergo accelerated atresia and get depleted before the age of 40, resulting in early menopause.
This leads to low serum estrogen and high FSH and LH. Finally, a structural cause of secondary amenorrhea is intrauterine adhesions, or Asherman syndrome, which is when there is scar tissue inside the uterine cavity, typically in a female that has undergone uterine instrumentation in the past.
Amenorrhea can occur because there is so much scar tissue that there’s no functional endometrium left, or because the presence of scar tissue makes the endometrium refractory to hormonal stimulation.

Symptoms9:18–10:39

The one symptom of both primary and secondary amenorrhea is, well, the absence of menstruation. Additional symptoms depend on the cause.
Individuals with Turner syndrome have a short stature, absent secondary sex characteristics, and a wide, or webbed, neck.
Müllerian agenesis might cause dyspareunia, or painful sexual intercourse, and infertility. With androgen insensitivity syndrome, individuals typically have sparse body hair, and little to no pubertal acne.
With Kallmann syndrome, there may be anosmia, or absent sense of smell, because the neurons responsible for olfaction are closely related to the ones that release GnRH.
With functional hypothalamic amenorrhea due to anorexia, there’s significant weight loss and decreased bone density and fractures.
With polycystic ovary syndrome, the ovarian follicles secrete too much testosterone, causing hirsutism, or excessive hair growth on the chin and upper lip, chest, and back.
With a prolactinoma, there might be galactorrhea, or abnormal milk production. With premature ovarian failure, there may be additional symptoms like hot flashes and vaginal dryness.
With intrauterine adhesions there could be infertility. First step in diagnosing primary or secondary amenorrhea is to rule out pregnancy with a pregnancy test.

Diagnosis10:39–11:23

If that’s negative, diagnosis requires serum levels of FSH, LH, estrogen, prolactin, TSH and testosterone. A karyotype can be done for Turner syndrome and androgen insensitivity syndrome.
An ultrasound can show if there are structural issues with the vagina or the uterus, which suggests Müllerian agenesis, or, if there is no uterus, and intra abdominal testicles are found, that suggests androgen insensitivity syndrome.
Intrauterine adhesions can be visualized through hysteroscopy. Treatment depends on the underlying condition.

Treatment11:23–12:07

Hormone replacement therapy, like combined oral contraceptives may be useful for individuals with Turner syndrome, polycystic ovarian syndrome or premature ovarian failure.
For a prolactinoma, dopamine agonists like cabergoline can be used - because they inhibit prolactin secretion just like dopamine naturally would, and they shrink the adenoma.
Surgery can be used to remove intrauterine adhesions, and to help correct some of the structural issues in Müllerian agenesis.
In some cases, psychotherapy can also be useful, as well as treatment for the related fertility issues. All right, as a quick recap… Amenorrhea is the abnormal absence of menstruation in females of reproductive age.

Review12:07–13:03

It can be primary, in which case menstruation never started, or secondary, in which case regular menstruation has stopped in a female who was previously menstruating.
Causes of primary amenorrhea include Turner syndrome, Müllerian agenesis, androgen insensitivity syndrome and endocrine disorders like Kallmann syndrome.
Causes of secondary amenorrhea can also cause primary amenorrhea, and they include functional hypothalamic amenorrhea, polycystic ovary syndrome, hyperprolactinemia, premature ovarian failure and Asherman syndrome.
Other associated symptoms, serum FSH, LH, estrogen and testosterone, as well as an ultrasound or a karyotype can be used to identify the underlying condition.