AssessmentsAmenorrhea: Pathology Review
USMLE® Step 1 style questions USMLE
A 35-year-old woman comes to the office with complaints of irregular menstruation. She has had only two periods in the last year. Menarche was at age 12, and she had a regular menstrual cycle until 12 months ago. The patient also reports feeling flushed at night without provocation and experiencing occasional dyspareunia with post-coital spotting. Past medical history is noncontributory. Temperature is 36.9°C (98.5°F), pulse is 70/min, respirations are 13/min, and blood pressure is 118/76 mmHg. Cardiopulmonary and abdominal exams are unremarkable. The patient has Tanner stage V breasts and pubic hair. Pelvic examination reveals a small anteverted uterus and minimal vaginal rugations. Abdominal examination is within normal limits. Urine pregnancy test is negative. Serum TSH is 3.2 µU/mL. Which of the following set of hormonal changes will most likely be observed in this patient?
Content Reviewers:Antonella Melani, MD
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.
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.
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.
Menarche, which refers to the first menstrual period, occurs during early adolescence or puberty, usually by the age of 15.
The monthly menstrual cycle can vary in duration from 20 to 35 days, with an average of 28 days.
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 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.
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.
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.
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.
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.
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.
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.
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.
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 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.
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.
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.
A test question may sometimes include a characteristic picture of a bulging, bluish hymenal membrane.
To confirm the diagnosis, an ultrasound can be done to spot the hematocolpos. Treatment is with surgical incision of the hymen.
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.
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.
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.
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