Approach to Secondary Amenorrhea

amenorrhea-secondary

Whereas Primary Amenorrhea is defined as a lack of menses in a woman who had never previously menstruated, Secondary Amenorrhea is:

  • Cessation of menses for 6 months, in a female who was previously menstruating.

The causes of Secondary Amenorrhea are different from those causing Primary Amenorrhea:

  • Pregnancy, lactation, menopause: 95%
  • Other causes: 5%
    • ↓gonadotrophic ↓gonadism: 66%
      • (including hypothalamic abnormalities, PCOS)
    • ↑ PRL: 13%
    • Ovarian failure: 12%
    • Anatomic abnormality: 7%
    • ↑ androgens: 2%

To evaluate Secondary Amenorrhea, a thorough history and physical exam are of course of vital importance. Since these patients by definition have menstruated in the past, the overriding question to answer is, “what is now stopping this patient from having menses?” In the vast majority of cases, normal pregnancy or menopause drives the amenorrhea. Many of the topics to discuss are the same as in the assessment of Primary Amenorrhea, but also talk to the patient about:

  • Symptoms of menopause: hot flushing, vaginal dryness, poor sleep, decreased libido
  • Obs/Gyn history: past endometritis, D&C, significant hemorrhage. These factors may point to a diagnosis of Asherman’s syndrome (scarring of endometrium).
  • Pregnancy: Potential for pregnancy, currently breastfeeding
  • Lifestyle factors such as stress, nutrition, exercise, weight changes
  • Medication: THC, antipsychotics, or irradiation
  • Associated symptoms:
    • Hyperprolatinemia: galactorrhea
    • Hyperandrogenism: hair loss/excess, acne, voice change
    • CNS tumor: headaches, visual field deficits, polyuria/polydipsia
    • Family history: PCOS

physical exam

  • Vitals, height, weight
  • Breasts: galactorrhea?
  • Thyroid: exopthalmos, goiter, abnormal deep tendon reflexes
  • Hyperandrogenism: hirsuitism, acne, hair loss
  • Hypercortisolemia: striae, hyperpigmentation
  • Pelvic exam

The labs used to work up Secondary Amenorrhea can be quite informative:

  • βHCG: To rule out pregnancy.
  • TSH, PRL: To test for hypo/hyperthyroidism and hyperprolactinemia.
  • LH, FHS: For practicality’s sake, these would probably be ordered at the same time as TSH, PRL.
    • If levels are high may indicate premature ovarian failure.
    • If levels are very low, that may point to a sellar tumor, so obtain an MRI.
    • If levels are normal, there may be a functional hypothalamic cause for the amenorrhea (e.g., malnutrition).
  • +/- Androgens (testosterone, DHEAS, 17-alpha-hydroxyprogesterone): May indicate PCOS or androgen-secreting tumor
  • +/- Estradiol: These assays lack sensitivity, standardization, and only capture a single time point.
  • Progestin challenge: To test the patient’s estrogen status. Administer a course of progesterone (~ 7 days).
    • If this results in bleeding, there is evidence the patient is progesterone deficient, anovulatory, or has an androgen excess.
    • If there is a lack of withdrawal bleeding, there are still a few causes to examine, so try the estrogen/progesterone challenge.
  • Estrogen/progesterone challenge: Give a course of estrogen/progesterone.
    • If there is withdrawal bleeding, it is apparent the patient has an estrogen deficiency.
    • If there is no bleeding in response to the challenge, the suspicion for an anatomic abnormality is heightened, so visualization of the uterus is indicated (e.g., hysteroscopy).

Treatment goals

  • Treat underlying cause
    • Lifestyle
    • Discontinue offending medications
    • Surgery (e.g., lysis of intrauterine adhesions)
  • Preserve fertility
  • Reduce risk of complications
    • Young women with premature ovarian failure can take hormone replacement to protect against early bone loss, menopause symptoms, and improve sexual health. These benefits may outweigh the associated increase in risk of MI, stroke, or breast cancer.

Master-Hunter T, Heiman DL. 2006. Amenorrhea: evaluation and treatment; 73:1374.
The Practice Committee of the American Society for Reproductive Medicine. 2008. Current approach to amenorrhea. Fertility and Sterility;90:S219.
Welt CK, Barieri RL. Etiology, diagnosis, and treatment of secondary amenorrhea. In: UpToDate (Eds: Snyder PJ, Crowley Jr WF, Kirkland JL). Accessed 2013.10.05.

Approach to Primary Amenorrhea

amenorrhea---primary

Primary Amenorrhea is defined as the absence of menses:

  • By age 13/14 without normal development of secondary sexual characteristics; OR,
  • By age 15/16, with normal secondary sexual characteristics.

In contrast, Secondary Amenorrhea refers to a loss of menses after it has already been established.

The causes of amenorrea are myriad, with an important one being pregnancy.

Causes of Amenorrhea
Hypothalamus Stress, malnutrition, exercise, lactation, immaturity, Kallmann syndrome
Pituitary Tumor, empty sella, apoplexy, hyperprolactinemia/prolactinoma
Ovaries Gonadal dysgenesis, premature ovarian failure, menopause, ovarian tumor, polycystic ovarian syndrome (PCOS), ovarian enzyme deficiency, chromosomal abnormalities (e.g., 45XO)
Uterus Intrauterine scarring, cervical agenesis, androgen insensitivity
Outflow Tract Imperforate hymen, transverse vaginal septum, cervical stenosis, Mullerian agenesis
Thyroid Hypo/hyperthyroidism
Pregnancy
Other Constitutional delay of puberty, hyperandrogenism, Cushing’s syndrome, medications

The most common pathologic causes of Primary Amenorrhea are:

  • Chromosomal abnormalities: 50%
  • Hypothalamic abnormalities: 20%
  • Mullerian agenesis: 5%
  • Pituitary abnormalities: 5%

Determining the etiology of Primary Amenorrhea depends on careful history-taking and a targeted physical exam. Key points to address in the history include:

  • Potential for pregnancy, current lactation
  • Develop of secondary sexual characteristics
    • On a side note, the general order of female sexual development is: breasts, pubic hair, growth spurt, menses; or, “boobs, pubes, grow, flow”
  • Lifestyle factors such as stress, nutrition, exercise, weight changes
  • Medication: THC, antipsychotics, or irradiation
  • Associated symptoms:
    • Hyperprolatinemia: galactorrhea
    • Hyperandrogenism: hair loss/excess, acne, voice change
    • CNS tumor: headaches, visual field deficits, polyuria/polydipsia
    • Family history: Does everyone have relatively late puberty?

In terms of physical exam:

  • Vitals, height, weight
  • Secondary sexual characteristics: breasts, pubic/axillary hair
  • Thyroid: exopthalmos, goiter, abnormal deep tendon reflexes
  • Hyperandrogenism: hirsuitism, acne, hair loss
  • Hypercortisolemia: striae, hyperpigmentation
  • Turner syndrome: webbed neck, low hair line, widely-spaced nipples, short stature
  • Pelvic exam: hymen, vaginal septum, ultrasound for uterine anatomy

Laboratory investigations can offer lots of insight:

  • βHCG: Gotta rule out this common reason first!
  • TSH, PRL: To test for hypo/hyperthyroidism and hyperprolactinemia.
  • LH, FHS: For practicality’s sake, these would probably be ordered at the same time as TSH, PRL.
  • +/- Androgens (testosterone, DHEAS, 17-alpha-hydroxyprogesterone): May indicate PCOS or androgen-secreting tumor, androhen insensitivity syndrome, or 5-alpha-reductase deficiency.
  • +/- Estradiol: These assays lack sensitivity, standardization, and only capture a single time point.

Since chromosomal abnormalities account for half of the pathologic cases of Primary Amenorrhea, karyotyping will be useful for patients who are found to have abnormal uterine anatomy on ultrasound or have elevated FSH, LH. Patients with an absent uterus may be worked-up for abnormal Mullerian development (46XX karyotype and normal female testosterone levels) versus a deficit in masculinization (i.e., androgen insensitivity syndrome, 5-alpha-reductase deficiency). There is a normal uterus, and LH and FSH are high, that means there is nothing feeding back to stop their release; karyotype may reveal Turner syndrome (45XO), while normal karyotype (46XX) may indicate Mullerian agenesis.

The over all treatment goals are to:

  • Treat underlying cause:
    • Lifestyle
    • Discontinue offending medications
    • Surgery
  • Preserve fertility
  • Reduce risk of complications (e.g., remove undescended tests in androgen insensitive patients to mitigate cancer risk).
  • Master-Hunter T, Heiman DL. 2006. Amenorrhea: evaluation and treatment; 73:1374.
  • The Practice Committee of the American Society for Reproductive Medicine. 2008. Current approach to amenorrhea. Fertility and Sterility;90:S219.
  • Welt CK, Barieri RL. Etiology, diagnosis, and treatment of primary amenorrhea. In: UpToDate (Eds: Snyder PJ, Crowley Jr WF, Kirkland JL). Accessed 2013.05.05.

The Menstrual Cycle

The menstrual cycle. What more of a classic drawing can you get? Though it has been done a million times over, here’s the Sketchy Medicine version of the classic hormonal interplay that allows for the endometrial lining to build up, shed, build up, shed, build up, shed…

The nice thing is the the pituitary hormones are aptly named so that FSH (follicle stimulating hormone) stimulates the follicle to grow and LH (luteinizing hormone) causes ovulation (the infamous LH surge) and subsequent corpus luteum development.

Meanwhile the developing follicle secretes estradiol which stimulates the proliferative phase of the cycle. Then the corpus luteum secretes estradiol and progesterone to kick things into high gear for the secretory phase.

Thyroid hormone differential

As with all of the pituitary axises, the thyroid one is a little confusing when people talk about it but really quite simple when it’s drawn out.

Hypothalamus -> Pituitary -> TSH -> Thyroid -> T4 & T3

Free T4 is what normally gets measured to determine if someone is hypo- or hyperthyroid, but if you are just doing a basic screening test, you only need to measure TSH.

In the image, black represents the gland not functioning, while red is it going wild and crazy. remember that primary is the END ORGAND (in this case the thyroid).

Things in flux simply means that you’ve measured someone’s levels while things were in the midst of a change. This is because T3 and T4 levels can change fairly quickly, but it takes a while for the pituitary to catch up. This can happen either in the case of one of the glands ceasing to function or the person has recently started medication to correct thyroid hormone levels and the thyroid has changed but the pituitary hasn’t.

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