Definitions

Amenorrhea means the absence of menstrual flows. It may be “Primary” or “Secondary.”

• Primary amenorrhea means the patient has never had a menstrual flow.
• Secondary amenorrhea means that she used to have menstrual flows, but they have stopped.

Normally, in the United States, menstruation will have begun by age 15, and if it hasn’t, that’s defined as primary amenorrhea.

But there are a couple of important additions to that general rule:

• If a 13 year old has never had a menstrual flow, and has no secondary sexual characteristics, such as breasts and pubic hair, then we would consider her to have primary amenorrhea.
• If a girl of any age hasn’t had a menstrual flow within 5 years of developing secondary sexual characteristics, she is considered to have primary amenorrhea.

Oligomenorrhea means infrequent menstrual flows. If a woman has fewer than 9 cycles per year, she is said to have oligomenorrhea.

Secondary amenorrhea means the absence of menses for at least 3 previous cycles or 6 months.² Pregnancy is the single most common cause of secondary amenorrhea.

Pathophysiology and Etiologies of Amenorrhea

For normal menstrual function to occur, a succession of properly communicated signals and functional end organs must be present.

• The hypothalamus must be intact and able to send GnRH signals to the anterior pituitary.
• After receipt of this signal, the anterior pituitary must be able to produce and deliver the follicle stimulating hormone and luteinizing hormone messages to the ovary.
• The ovary must be normal with an adequate number of follicles, and a uterus must be present with a lining that is capable of responding to the sex hormones created by the ovary.
• Finally there should be an unobstructed path for the uterine menstrual blood to be delivered to and through the vagina.

So when investigating the cause for either primary or secondary amenorrhea, we must consider the possibility of an abnormality in any of these areas critical for normal menstrual function:

• The Hypothalamus and Central Nervous System
• The Anterior Pituitary
• The Ovary and
• The uterus and genital outflow tract. 

Disorders of the Hypothalamus

Functional Hypothalamic Amenorrhea

There are two clinically important disorders of the hypothalamus:

• Functional Hypothalamic Amenorrhea, and
• Kallman Syndrome

If energy demand is high (with excessive exercise) or supply is low (eating disorder), the body will favor shifting its resources away from reproduction and towards other critical processes. This is what happens with Functional Hypothalamic Amenorrhea, or FHA.

Extremes of weight, stress, and physical activity are thought to cause reproductive restraint through abnormal secretion of GnRH, as well as increases in CRH and cortisol, which can also inhibit gonadotropin secretion.

Functional hypothalamic amenorrhea (FHA) is a diagnosis of exclusion, but one that should be considered in the setting of a hypogonadal state, normal to low gonadotropin levels, and in the absence of any sellar mass on brain imaging.

The majority of women who suffer from FHA either report frequent or strenuous exercise, rapid weight loss, or are themselves ≥10% below their ideal body weight. If an eating disorder, such as anorexia nervosa or bulimia, is suspected, a multi-disciplinary approach involving a mental health specialist, physician, and nutritionist should be taken.

Not all exercise is the same. Exercise regimens that lead to low body weight, such as running, ballet, ice-skating and gymnastics, are linked to a greater chance for amenorrhea.

The most serious complication of hypothalamic amenorrhea is bone loss, thus a baseline DEXA scan should be considered following diagnosis.

For women with eating disorders, weight gain is critical as hormone therapy alone is not sufficient in restoring bone density.

Women with exercise-induced amenorrhea should be counseled about reducing the intensity, frequency or duration of their exercise regimen to reduce their risk for bone loss and fracture. Hormone therapy can be considered for this group, along with supplemental vitamin D and calcium.

Kallman Syndrome

A rare cause of hypothalamic amenorrhea is congenital GnRH deficiency.

Although a number of genetic aberrations have been linked to this disorder, the classic X linked type, which is associated with a mutation in the KAL gene, is associated with a loss of one’s sense of smell.

The KAL gene is responsible for transcribing the anosmin protein, a molecule responsible for the migration of olfactory neurons and GnRH neurons from the olfactory placode to the hypothalamus during embryogenesis.

Patients with this condition generally present with delayed puberty and have a family history of the syndrome.

Since adrenarche occurs independent of the maturation of the hypothalamic-pituitary-ovarian access, pubic hair is generally present, while breast development and menstrual flows are absent.

The main laboratory findings are very low or undetectable levels of LH and FSH, low estrogen, a normal karyotype and absence of other causes of amenorrhea.

Although sequencing of the KAL gene may lead to definitive diagnosis, but as there are likely many unknown genetic etiologies for Kallman, a negative result cannot exclude the diagnosis.

Treatment involves hormone therapy for both pubertal initiation and bone protection.

Disorders of the Pituitary

Elevated Prolactin Levels or Hyperprolactinemia

The important pituitary disorder related to amenorrhea is hyperprolactinemia.

Because prolactin inhibits the GnRH pulse generator, elevations in prolactin can also cause a hypothalamic state.

Patients may present with shortened luteal phase, oligomenorrhea, or amenorrhea, galactorrhea, and occasionally headache or visual changes.

Prior to testing, the patient should be advised to fast, to abstain from intercourse, and to avoid exercise, as these activities can lead to a false positive result.

If persistently elevated prolactin levels are found, the next step is to determine the etiology. Typically, hyperprolactinemia is caused by primary thyroid dysfunction, medications (more often dopamine inhibitors), or prolactin producing pituitary adenomas. Thus, evaluation includes thyroid function testing, review of medications, and a brain MRI.

Correction of the thyroid disorder will lead to restoration of normal prolactin levels and resolution of hyperprolactinemic symptoms. If an anti-psychotic medication is the cause, it is best to coordinate the patient’s care with her primary mental health professional. Strategies may include transitioning the patient to an alternative medication.

Dopamine agonists are the primary treatment for lactotroph adenomas of all sizes, however special attention should be given to women with

• macroadenomas (greater than 10 millimeters),
• tumors that do not reduce in size following normalization of prolactin levels (which may suggest a nonfunctioning adenoma), or
• those that rapidly grow and cause significant neurologic deficit (suggesting a malignancy).

Women should be followed closely with serial prolactin measurements and repeat brain imaging to assure resolution.

Disorders of the Ovary

Polycystic Ovary Syndrome

Let’s consider some problems with the ovaries that can lead to amenorrhea.

Although listed as a disorder of the ovary, the polycystic ovary syndrome is a complex disorder stemming from abnormal GnRH secretion and leading to intra-ovarian hyperandrogenism and abnormal folliculogenesis.

Cyclical release of LH and FSH from the anterior pituitary stimulates the granulose and thecal cells of the ovary to produce estrogens, androgens and progesterone in varying amounts, leading to ovulation, all in support of the monthly opportunity for a pregnancy.

In PCOS, the normal rise and fall of the gonadotropins doesn’t occur. Because abnormal GnRH pulsatility favors LH release over FSH release, increased thecal androgen production occurs.

Insulin resistance can also contribute to increased ovarian androgen production and hyperandrogenemia as insulin acts synergistically with LH and suppresses hepatic sex hormone binding globulin production.

Elevated local androgen prevents normal folliculogenesis and the result is the appearance of polycystic ovaries on ultrasound.

For the diagnosis of PCOS, the patient should meet two of three of the following conditions, known as the Rotterdam Criteria:

1. Oligo- or anovulation
2. Clinical and or biochemical evidence of hyperandrogenism and
3. Ultrasound evidence of polycystic ovaries.The sonographic definition of polycystic ovaries includes the presence on one ovary of at least 12 antral follicles or a total ovarian volume of at least 10 cc. As many as 20% of normal women have this ultrasound finding without having the syndrome.

Patients with PCOS are at risk for insulin resistance, diabetes mellitus, metabolic syndrome, endometrial hyperplasia and cancer, obstructive sleep apnea, and depression.

Because about half of women with PCOS are obese, and because obesity is associated with the long-term cardio-metabolic risks of PCOS, the most important initial and maintenance treatment are the lifestyle changes of a healthy diet and exercise. A 2-5% reduction in weight can reduce metabolic risk and improve reproductive potential.

If fertility is not desired, the progestins found in oral contraceptives, cyclic provera, or the mirena IUD can be used to protect the endometrium from hyperplasia.

In women seeking fertility, ovulation induction agents, such as clomiphene citrate, can be used.

In women complaining of androgen excess (hair and acne) and not currently seeking a pregnancy, oral contraceptive pills can effectively reduce androgens. Anti-androgens can also be used.

Gonadal dysgenesis

Structural or numerical sex chromosome abnormalities can cause gonadal dysgenesis, ultimately leading to abnormal gonadal formation and the appearance of “streak gonads.”

Often this occurs in utero or in the first few years of life, and is the most common cause of primary amenorrhea.

Affected girls usually present with primary amenorrhea or pubertal delay as well as elevated FSH levels and low estradiol levels. As adrenarche is driven by the adrenal gland, which is unaffected, pubic hair may still be present.

The key initial step to determining the cause for ovarian failure in the setting of primary amenorrhea is by obtaining a karyotype. Although 25% of patients will have a normal 46 XX karyotype, Turner syndrome must also be ruled out.

Turner Syndrome

Turner syndrome, the most common form of gonadal dysgenesis, is associated with a 45, X karyotype. Physical examination may reveal the classic Turner phenotype, which includes a webbed neck, shield chest, and cubitus valgus.

Because patients with Turner syndrome are at increased risk for coarctation of the aorta, hearing loss, thyroid dysfunction, metabolic syndrome and celiac disease, they should undergo routine surveillance for these conditions.

Treatment is aimed at improving final adult height with growth hormone, as well as initiating puberty and maintaining bone protection with hormone therapy.

Premature Ovarian Insufficiency

Cessation of menstrual function, or menopause, normally occurs around age 51, but with premature ovarian insufficiency, it may occur at a much younger age.

The diagnosis of premature ovarian insufficiency involves amenorrhea or menstrual irregularity as well as menopausal levels of follicle stimulating hormone on two different occasions 4-6 weeks apart.

Patients may present with menopausal symptoms, such as hot flushes, vaginal dryness, and menstrual irregularity. Carrier status for fragile X permutation and assessment of thyroid and adrenal autoimmunity should be obtained in addition to a karyotype; a baseline DEXA scan can also be considered.

Similar to young girls with gonadal dysgenesis, treatment is centered around hormone therapy for bone protection.   

Ovarian Surgery, Chemotherapy, Radiation therapy

Other causes of late gonadal failure include gonadal surgery, or a history of chemotherapy and radiation.

Multiple excision procedures which reduce ovarian stroma, or a prior history of bilateral salpingo-oophorectomy, can lead to amenorrhea and the diagnostic picture appears similar to gonadal failure.

Chemotherapy and pelvic radiation can also lead to a reduction in the number of eggs and subsequently lead to amenorrhea. The effect is largely dependent on the type of agent used, the dose, and duration of treatment.

Although fertility preservation procedures, such as in vitro fetrtilization or oocyte cryopreservation, prior to gonadotoxic therapy can help future fertility, hormone therapy is still required if gonadal failure is encountered.

Importantly, all patients with gonadal failure should be offered emotional support and the option for counseling.

Disorders of the Genital Outflow tract

Now, let’s consider disorders of the genital outflow tract.

Imperforate Hymen

Girls with imperforate hymen generally present with primary amenorrhea, normal secondary sexual characteristics, and cryptomenorrhea, or cyclic abdominal pain without menses. On examination, a thin, bulging, blue membrane just proximal to the introitus can be seen. Treatment involves surgical correction: generally, a cruciate incision is made in the redundant tissue, which is then excised and the hymeneal ring restored.

Transverse Vaginal Septum

A transverse vaginal septum can form if the mullerian ducts improperly fuse during embryogenesis.

This condition is far more rare than imperforate hymen, occurring in 1/20000-1/80000 women.

Girls with a transverse vaginal septum typically present with primary amenorrhea, normal secondary sexual characteristics, and cryptomenorrhea. The main difference between this and an imperforate hymen is the physical exam.

Unlike imperforate hymen, girls with transverse vaginal septum have a normal introitus and ruptured hymen, and what appears to be a blind ending vaginal pouch and no visible cervix. A Valsalva maneuver can be helpful in also distinguishing the two, as the introitus distends in those with imperforate hymen but not in those with transverse vaginal septum. Pelvic MRI confirms the diagnosis.

Surgical resection is best done by a surgeon with expertise in mullerian anomalies.

Mullerian Agenesis (Mayer Rokitansky Juster Hauser Syndrome, MRKH Syndrome)

The most common cause of primary amenorrhea in the presence of normal secondary sexual characteristics is mullerian agenesis, also known as Mayer Rokitansky Kuster Hauser or MRKH syndrome.

In this disorder, all or part of the uterus and vagina are absent and girls present with primary amenorrhea, normal female secondary sexual characteristics, and findings of a blind ending vaginal pouch.

Unlike transverse vaginal septum, these patients do not present with cryptomenorrhea, but like the former a pelvic MRI will make the diagnosis.

A higher risk for urogenital malformation is also associated with the syndrome and should be evaluated once the diagnosis is confirmed. Treatment involves counseling and emotional support along with the creation of a neovagina through successive vaginal dilation or surgical construction.

Androgen Insensitivity Syndrome

Complete androgen insensitivity syndrome (or AIS) presents similarly to MRKH syndrome, with normal female secondary sexual characteristics, primary amenorrhea and a blind ending vaginal pouch. However, it is more rare.

In this disorder, genetic males have abnormal androgen receptors, which ultimately leads to an absence of virilization and a female phenotype coupled with scant pubic hair.

Inguinal masses may also be present, representing the underdeveloped testes. Serum androgen levels and a karyotype are key to distinguishing these two diagnoses.

As in the case of MRKH Syndrome, those with AIS will benefit from counseling, social support and consideration of creation of a neovagina.

Unlike MRKH, gonadectomy should be performed following puberty in those with a diagnosis of AIS to avoid the formation of gonadoblastoma.

Asherman Syndrome and Cervical Stenosis

Anatomic defects associated with secondary amenorrhea include cervical stenosis and Asherman syndrome, in which the endometrial cavity is scarred.

Historical clues include a prior history of cervical dysplasia requiring multiple excision procedures or postpartum dilation and curettage in the setting of postpartum hemorrhage.

Generally, a diagnosis can be made using physical exam for the former and saline infusion sonohysterogram for the latter. Treatment usually involves cervical dilation or hysteroscopic lysis of adhesions.

Evaluation

In cases of primary amenorrhea, it is important to assess if and at what age other pubertal milestones have been reached, such as breast and pubic hair development. A typical exam should also include Tanner staging of breast development and pubertal hair distribution as well as a pelvic exam.

The most important initial step is to determine if there is any clinical or biochemical evidence of estrogen. This can be done through Tanner staging on physical exam (is there breast development?) or response following a progestin challenge test (does the patient bleed after a short course of progestin therapy?).

We can narrow the differential diagnosis further based on the results of 3 additional blood tests: Follicle Stimulating Hormone (FSH), Leutinizing hormone (LH) and Estradiol, which are helpful in determining the causes for both primary and secondary amenorrhea. The exception to this rule is polycystic ovary syndrome, in which isolated elevations in LH can be seen or a eugonadotropic state can be seen.

The key diagnostic components of an amenorrhea evaluation should include a thorough physical exam along with

• Serum Pregnancy Test
• Pelvic ultrasound or MRI
• Serum FSH, LH, and estradiol
• Serum fasting prolactin
• Serum TSH and FT4
• Brain MRI (to rule out hypothalamic or pituitary space occupying lesion, and to rule in functional hypothalamic amenorrhea)
• Karyotype (If hypergonadotropic hypogonadism is encountered, or to distinguish between MRKH and AIS)
• Total Testosterone levels (To rule in PCOS or AIS)

References

¹Current evaluation of amenorrhea. The Practice Committeee of the American Society for Reproductive Medicine. Fertility and Sterility. 2008. 90(3):S219-S225.

²Fritz M. Clinical Gynecologic Endocrinology and Infertility. Philadelphia: Lippincott Williams & Wilkins, 2011. Print.

³Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 1:19-25.