Amenorrhea: Secondary

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Introduction0:00–0:47

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.

Physiology0:47–1:43

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 3 months.

Pathology1:43–2:18

Second, it can mean a person who used to have irregular menstruation stops having it for at least 6 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.

Functional hypothalamic amenorrhea2:18–5:00

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, cause 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. In 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 in 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.

PCOS5:00–7:45

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 thecus cells around the ovarian follicle also have insulin receptors. When insulin stays high, it stimulates thecas 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 feca cells and more LH receptors, LH has a much stronger effect, pushing feca cells to release large amounts of androstendiion.
Next, the body converts androstendiion 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.
Diagnosis primarily relies on imaging and lab tests. A pelvic ultrasound reveals enlarged ovaries filled with multiple small unruptured follicles that look like cysts.
Labs indicate an elevated LH to FSH ratio, as well as high androgen levels. These high androgens cause key clinical features of PCOS like acne and hirsutism, or hair growth on the chin and upper lip, chest and back.
Finally, treatment involves weight loss and oral contraceptives. For those who desire to become pregnant, clomiphene can help induce ovulation.
Next up is hyperprolactinemia, which means high prolactin levels in the blood. Normally during pregnancy and breastfeeding, the pituitary gland pumps out more prolactin to support milk production.

Hyperprolactinemia7:45–9:28

However, when someone isn't pregnant or breastfeeding, the hypothalamus sends dopamine down through the pituitary stalk to the pituitary, inhibiting prolactin production.
The problem starts when there is no pregnancy or breastfeeding, but the pituitary gland goes off track and produces prolactin.
This can happen because of a benign tumor called a prolactinoma. Also, tumors that press on the pituitary stalk, like craniopharyngioma, can block the dopamine signal that normally keeps prolactin in check.
Lastly, anti-dopaminergic medications like haloperidol and risperidone block dopamine receptors, allowing prolactin levels to rise.
No matter the cause, hyperprolactinemia inhibits the release of GNRH from the hypothalamus, shutting down the hypothalamic pituitary ovarian axis, and eventually causing amenorrhea, an ovulation, and even infertility.
Diagnosis relies on labs, which reveal high prolactin levels. Once you rule out medication-induced hyperprolactinemia, be sure to order imaging like brain MRI to check for tumors.
Treatment involves dopamine agonists, such as bromocriptine or cabergoline to inhibit prolactin secretion, and if there is a pituitary tumor, surgery is the way to go.
Finally, let's go over primary ovarian insufficiency, or premature ovarian failure, which occurs when ovarian follicles stop functioning, resulting in early menopause before the age of 40.

Primary ovarian insufficiency9:28–11:01

In most cases, primary ovarian insufficiency is idiopathic, meaning there's no clear cause. However, it can also result from chemotherapy, radiotherapy, or autoimmune conditions.
And if it occurs at a younger age, it might be linked to Turner syndrome or fragile X syndrome. Two theories explain why primary ovarian insufficiency might occur.
The first is follicle depletion, which suggests that some individuals have a low starting number of follicles, or their follicles degenerate too quickly.
As a result, they run out of eggs too soon. The second theory suggests there are enough follicles, but the ovaries can't respond to FSH and LH, so they can't produce estrogen, causing the menstrual cycle to break down.
Diagnosis relies on labs, which reveal low estrogen and high FSH and LH because the pituitary is trying to compensate for ovarian failure.
Also, don't forget karyotype testing to rule out Turner syndrome and fragile X syndrome. Finally, treatment involves hormone replacement therapy.
All right, as a quick recap, functional hypothalamic amenorrhea happens when stress, extreme exercise, or low body fat shuts down the hormone signals that start the menstrual cycle.

Review11:01–11:44

PCOS is associated with insulin resistance and hormone imbalances that stop eggs from maturing properly, leading to cysts and amenorrhea.
Next, hyperprolactinemia occurs when prolactin levels get too high, which shuts down the hypothalamic pituitary ovarian axis.
Finally, primary ovarian insufficiency means the ovaries stop working early, resulting in early menopause before the age of 40.