Amenorrhea

This article provides an approach to amenorrhea and is intended for pre-clinical and clerkship medical students. Primary amenorrhea refers to the absence of menarche by 15 years or 3 years post thelarche while secondary amenorrhea is the cessation ofmenses for 3months inwomen with a previously regular cycle or for 6 months in women with previously irregular menses. While amenorrhea can be physiological it can also reflect an anatomical or more complex hormonal problem that students must learn to identify and investigate.


| QUESTION
year-old girl presents to your office. Her primary concern is that she is shorter than her classmates. She mentions she has had hearing difficulties since childhood, and is known for a heart defect and scoliosis. She is concerned about being the only one in her not having had her period yet. On physical exam, the patient is short in stature with no physical signs of pubertal development. You also notice that she has low set ears and a low hairline. Initial laboratory results are as follows:

| INITIAL APPROACH
The initial investigation of a patient presenting with amenorrhea begins with a thorough history and physical examination. First, it is important to differentiate between primary and secondary amenorrhea.

| Beta Human Chorionic Gonadotropin
The first step in the evaluation of amenorrhea is to exclude pregnancy because it is the most common cause of amenorrhea in women of reproductive age.

| Prolactin
Hyperprolactinemia is the most common cause of secondary amenorrhea after pregnancy and is diagnosed when serum levels of PRL exceed 25µg/L.

| Pelvic Ultrasound
Anatomical defects should always be considered in the differential diagnosis of primary amenorrhea. Women presenting with primary amenorrhea should be evaluated for the presence of a uterus and vagina by pelvic US. These two conditions can be differentiated by karyotyping or measuring serum testosterone ( Figure 1, Table 1).
Outflow tract obstructions such as an imperforate hy-men or a transverse vaginal septum often present with cyclic pain and may be the cause of amenorrhea in the presence of a normal uterus. (3,11) Pelvic US is also relevant in the investigation of secondary amenorrhea to assess for ovarian pathology as well as PCOS. Intrauterine adhesions and cervical stenosis resulting from endometrial instrumentation and cervical procedures also need to be considered in the differential diagnosis of secondary amenorrhea. (3,11) F I G U R E 1 Hypothalamic-pituitary-ovarian axis. Depending on the level of dysfunction within the HPO axis, the serum levels of FSH and LH will be different. When the defect is downstream at the level of the ovaries, FSH and LH levels will be elevated in the absence of negative feedback from the gonads (hypergonadotropic hypogonadism). When the defect is more upstream (hypothalamus or pituitary), the patient will suffer from HH and the serum levels of FSH and LH will be low.

| Follicle-stimulating Hormone, Luteinizing Hormone and Estradiol
Independent of the classification of the patient's amenorrhea as primary or secondary, the remaining causes can be divided into normogonadotropic, hypergonadotropic or HH, depending on FSH and LH serum values (Table 1). FSH, LH and estradiol levels will be increased or decreased depending on which component of the hypophyseal-pituitary-ovarian (HPO) axis is dysfunctional ( Figure 2). Normal values of FSH and LH are between 5-20mIU/mL, but LH levels can increase up to 40mIU/mL during the LH surge 24h prior to ovulation (11,12). Normal values of estradiol vary between 30-

| BEYOND THE INITIAL AP-PROACH
In this section, important causes of amenorrhea are discussed in more detail, including further steps in patient management and treatment.

| Polycystic Ovary Syndrome
PCOS is the most common cause of infertility in women and is a major cause of hyperandrogenic amenorrhea. It is important to note that etiologies of secondary amenorrhea can also be the cause of primary amenorrhea. If the patient has a uterus, the evaluation of primary and secondary amenorrhea is similar following history and physical examination. Note that in real life, FSH and LH levels are often measured with TSH and PRL not to delay diagnosis.
Adapted from: Amenorrhea: A systematic Approach to Diagnosis and Management, AAFP. https://www-aafp-org.proxy3.library.mcgill.ca/afp/2019/0701/afp20190701p39.pdf Using an algorithmic approach to secondary amenorrhea: Avoiding diagnostic error, Clinica Chimica Acta. https://pdf.sciencedirectassets.com/271330/1-s2.0-S0009898113X00075/1-s2.0-S0009898113001411/main.pdf should be placed on the presence of underlying anxiety or mood disorders and a bone density scan may be indicated for women with amenorrhea lasting for more than 6 months. (12) Amenorrhea is usually reversible, and treatment depends on the cause but mostly relies on adequate nutritional status, stress reduction and treatment of underlying psychiatric disorders.