Amenorrhea: Pathology review

Two people come to the clinic one day. First you see Ana, a 17 year old teenage girl. Ana comes with her mother, who’s worried because Ana hasn’t had her first period yet.

Upon physical examination, you notice that Ana is quite short for her age. In addition, she has a wide neck, broad chest, and poorly developed breasts with widely spaced nipples. You decide to perform a blood test, which reveals low estrogen levels and high FSH and LH.

Next, comes María, a 25 year old female who’s concerned because she hasn’t had her period for nine months now.

She’s sexually active, so the first thing you do is ask for a pregnancy test, which comes up negative.

When asked about physical activities, she refers to going for a 2-hour run every single day, plus swimming and then tennis on weekdays.

Regarding her diet, she’s very strict when it comes to avoiding fatty foods. On physical examination, you realize that María is underweight, and a blood test reveals low levels of estrogen, LH, and FSH.

Okay, now both Ana and María have amenorrhea, which is generally defined as the absence of menstruation in females of reproductive age.

Now, for menstruation to happen, an individual must have a regular female reproductive anatomy and sexual development, which is normally under control of the hypothalamic-pituitary-gonadal axis.

First, the hypothalamus secretes gonadotropin-releasing hormone, or GnRH for short, which goes to the anterior pituitary to stimulate the release of gonadotropic hormones, which are luteinizing hormone or LH, and follicle-stimulating hormone or FSH.

LH and FSH then stimulate the gonads to produce sex hormones; in females, LH and FSH stimulate the ovaries to secrete estrogen and progesterone, which are responsible for the female primary sexual characteristics.

These are the changes necessary for reproduction, including menstruation, ovulation, and uterine development.

LH and FSH are also responsible for the development of secondary sex characteristics that aren’t required for reproduction, like breast development, hip widening, and hair growth mainly on the axillae and genital areas.

Now, once sex hormones have done their job, they signal the hypothalamus and pituitary to turn off the secretion of GnRH, FSH, and LH.

Menarche, which refers to the first menstrual period, occurs during early adolescence or puberty, usually by the age of 15.

Following menarche, the menstrual cycle recurs on a monthly basis until a person reaches menopause, pausing only during pregnancy.

The monthly menstrual cycle can vary in duration from 20 to 35 days, with an average of 28 days.

Each menstrual cycle begins on the first day of menstruation, and this is referred to as day one of the cycle.

During the menstrual cycle, the ovaries and the endometrium each undergo their own set of changes, which are separate but related.

Now, the first two weeks of the menstrual cycle is called the preovulatory or follicular phase, and this corresponds to the menstrual and proliferative phases of the endometrium.

During this phase, the pituitary mainly secretes FSH, which stimulates follicles scattered throughout the ovaries to start developing and secreting estrogen.

The increased estrogen levels act as a negative feedback signal, telling the pituitary to secrete less FSH. As a result, some of the developing follicles in the ovary will regress and die off.

However, the follicle that has the most follicle stimulating hormone receptors, will continue to grow, becoming the dominant follicle that will eventually undergo ovulation.

Now, estrogen levels start to steadily climb higher and higher, the estrogen from the dominant follicle now becomes a positive feedback signal; that is, it makes the pituitary secrete a whole lot of FSH and especially LH.

This surge stimulates ovulation, which is the rupture of the dominant follicle to release the oocyte, so the secretion of estrogen decreases.

Meanwhile, the uterus is preparing the endometrium for implantation and maintenance of pregnancy.

This process begins with the menstrual phase, which is when the old endometrial lining from the previous cycle is shed and eliminated through the vagina, producing the bleeding pattern known as the menstrual period.

The menstrual phase is followed by the proliferative phase, during which high estrogen levels stimulate thickening of the endometrium, as well as emergence of spiral arteries to feed the growing functional endometrium.

Following ovulation, the remnant of the ovarian follicle becomes the corpus luteum. So the two weeks following ovulation is referred to as the postovulatory or luteal phase.

This corresponds to the secretory phase of the endometrium, where the uterine glands begin to secrete more mucus.

Now, the corpus luteum secretes estrogen, which rises again, as well as lots of progesterone, which acts as a negative feedback signal on the pituitary, decreasing release of FSH and LH.

Over time, the corpus luteum gradually degenerates into the nonfunctional corpus albicans.

The corpus albicans doesn’t make hormones, so estrogen and progesterone levels slowly decrease.

When progesterone reaches its lowest level, the spiral arteries collapse, and the endometrium prepares to shed through menstruation.

This shedding marks the beginning of a new menstrual cycle and another opportunity for fertilization. Okay now, amenorrhea can be classified as primary or secondary.

Primary amenorrhea is when a female over the age of 15 hasn’t had her first menstruation, or menarche, despite normal growth and development of secondary sexual characteristics; or when a female over the age of 13 has neither had her menarche nor developed any secondary sexual characteristics.

For your exams, some high yield causes of primary amenorrhea include Turner syndrome, müllerian agenesis, and imperforate hymen.

On the other hand, secondary amenorrhea is when a female who used to have regular menstrual cycles stops having them for at least three consecutive months, or for six months in a female who used to have irregular menstrual cycles.

Most often, secondary amenorrhea is caused by natural processes, such as pregnancy, menopause, and breastfeeding.

However, in some cases, secondary amenorrhea can be caused by an underlying disorder.

For your exams, the most important is a hormonal imbalance at any level of the hypothalamic-pituitary-ovarian axis, such as functional hypothalamic amenorrhea; hyperprolactinemia; and polycystic ovarian syndrome or premature ovarian failure.

Other less frequently tested hormonal disorders that may cause secondary amenorrhea include Cushing syndrome, which is an endocrine disorder that involves high levels of cortisol; as well as thyroid disorders like hyperthyroidism, where the thyroid gland produces too much thyroid hormones, or hypothyroidism, where the thyroid doesn’t make enough hormones.

Now, keep in mind that all these underlying disorders may also occur before menarche, in which case they would lead to primary amenorrhea.

All right, so let’s dive into the causes of primary amenorrhea. The most common cause is Turner syndrome, which is characterized by having 45 chromosomes with only one X chromosome.

In most cases, this happens when a nondisjunction event occurs during meiosis of the paternal gamete, so that the sperm cell lacks a sex chromosome.

Conversely, if the nondisjunction occurs after formation of the zygote during mitosis, the result is a mosaic karyotype, meaning that some cells are 45,X and others are 46,XX.

For your exams, you should recognize some clinical features that are characteristic for Turner syndrome. Firstly, infants may have a variety of congenital malformations.

These can include a horseshoe kidney, which is when the two kidneys fuse at the bottom, forming a U shape; as well as cardiovascular abnormalities, like bicuspid aortic valve and coarctation or narrowing of the aorta, which are the most common causes of death in childhood.

Another very common finding in infants are lymphatic defects, such as lymphedema or swelling of the hands and feet.

Many also develop a cystic hygroma, which is an abnormal swelling on the back of the baby’s neck due to lymphatic fluid build up, which eventually decreases as they age.

This often leaves extra skin on the neck, called a webbed neck that’s wider than normal.

Additionally, mosaic individuals with some 46,XY cells are at increased risk for gonadoblastoma, which is a complex neoplasm of gonadal components.

Now, the X chromosome also carries genes that are important for growth and development of tissues throughout the body.

One of these is the short stature homeobox - SHOX for short - gene. So having a single copy of the SHOX gene results in, you guessed it, short stature.

Other characteristic features include a shield chest, which is when the individual has a broad chest and extensively spaced nipples.

Additional features include shortened fourth metacarpals or ring fingers, low set ears, and arms that turn outward at the elbows, also called cubitus valgus.

During puberty, there’s minimal pubic hair, breast, and uterine development, as well as ovarian dysgenesis or abnormal development, leading to streak ovaries, which develop white atrophic fibrous strands.

As a result, females with Turner syndrome produce decreased levels of estrogen, which leads to increased levels of both LH and FSH.

Because of this, Turner syndrome is the most common cause of primary amenorrhea, and thus individuals are said to reach ‘menopause before menarche’.

As a consequence, many females with Turner syndrome are infertile. Keep in mind though that pregnancy may be possible in some cases through in-vitro fertilization or treatment with exogenous estradiol-17β and progesterone.

Diagnosis of Turner syndrome can be confirmed via karyotype analysis, and treatment usually involves growth hormone therapy during childhood to promote bone growth, as well as sex hormone replacement therapy starting at puberty to promote breast and uterine development.

Moving on, the second most common cause of primary amenorrhea is Müllerian agenesis, which is also called Mayer-Rokitansky-Kuster-Hauser syndrome.

Okay, normally, during the first trimester of fetal life of a female baby, there’s a pair of ducts, called the paramesonephric or Mullerian ducts, which develop into the uterus, cervix, and upper two thirds of the vagina.

In Müllerian agenesis, the Müllerian ducts don’t develop properly. As a result, these organs may be absent, or rudimentary and obstructed, leading to primary amenorrhea, as well as dyspareunia, or painful sexual intercourse, and infertility.

However, the ovaries develop normally, and the hypothalamic-pituitary-ovarian axis is perfectly functional.

So individuals with Mullerian agenesis have fully developed secondary sexual characteristics, and this is a key difference from Turner syndrome.

Now, for diagnosis of Müllerian agenesis, an ultrasound can show if there are anatomical abnormalities involving the uterus or vagina, and treatment usually aims at correcting some anatomical issues using vaginal dilators or surgery.

Another rare but frequently tested cause of primary amenorrhea is an imperforate hymen.

Typically, the hymen is a thin half moon shaped membrane that partially covers the external opening of the vagina.

Now, an imperforate hymen results when the hymen central epithelial cells fail to degenerate during fetal development.

This leaves a hymenal membrane that completely covers the vaginal opening, blocking it.

At birth, an imperforate hymen may cause vaginal mucus to build up, causing the hymenal membrane to bulge outwards. Fortunately, that’s usually self-resolving!

The most high yield symptom occurs during puberty, when there’s primary amenorrhea because menstrual blood can’t flow out of the vagina.

As a result, menstrual blood accumulates in the vagina, which is also known as hematocolpos.

A test question may sometimes include a characteristic picture of a bulging, bluish hymenal membrane.

What’s important to note here is that individuals do experience recurring menstrual cramps and abdominal or pelvic pain, since they do have a normal menstrual cycle.

To confirm the diagnosis, an ultrasound can be done to spot the hematocolpos. Treatment is with surgical incision of the hymen.

All right, now let’s take a look at some causes of secondary amenorrhea. A natural cause you must absolutely remember is menopause, which is the permanent stopping of menstrual cycles.

To be more specific, menopause is officially diagnosed after twelve months of amenorrhea, so when an entire year has passed since the last menstrual period.

This usually happens at around the age of 50, but keep in mind that it could occur earlier in smokers.

Now, menopause is usually preceded by perimenopause, which is a transition period that typically lasts about four to five years.

During perimenopause, the ovaries have a lot less functional follicles, so there may be abnormal menstrual cycles characterized by irregular or missed periods.

And fewer follicles also means less production of estrogen and progesterone, so less inhibition on the hypothalamus and the pituitary.

In turn, the hypothalamus and pituitary produce more GnRH, LH, and especially FSH. These hormonal changes can cause a bunch of symptoms like hot flashes and night sweats, which can lead to sleep disturbances.

In addition, individuals may experience vaginal atrophy and dryness, which can lead to dyspareunia; as well as hirsutism, which refers to an excessive body hair growth in a male-like pattern that mainly involves the face, chest, and back.

Finally, estrogen normally has a protective effect on both the cardiovascular system as well as the skeleton.

So, low levels of estrogen can lead to complications like coronary artery disease and osteoporosis.

The good news is that the body can adjust to the hormone changes, so they actually go away on their own after a couple of years. In the meantime, menopausal hormone therapy can help alleviate these symptoms.