Primary Amenorrhea: A Comprehensive Overview
- Abiya Syed
- Jun 27, 2024
- 8 min read
Updated: Jul 29, 2024
Primary amenorrhea is the failure to reach menarche, or the first menstrual cycle, in a female of reproductive age.[1] It can be diagnosed in two cases, provided the patient is not pregnant (as confirmed by a pregnancy test): the patient has normal secondary sexual characteristics but no menstruation at age sixteen, or the patient has no secondary sexual characteristics by age fourteen.[2]
Once primary amenorrhea is diagnosed, healthcare providers typically try to ascertain the cause. This is because the disorder can be caused by a variety of factors, and treatment is highly dependent on what caused it in the first place. Differential diagnosis, or the process of differentiating between conditions that share similar symptoms, is used to determine the cause and start the treatment.[3]
Adapted from "Amenorrhea: A Systematic Approach to Diagnosis and Management (2019)"
Absence of Uterus in Primary Amenorrhea
A pelvic ultrasound is taken to establish the presence of the uterus. If the uterus is not present at all, or abnormal, the healthcare provider will conduct a karyotype analysis, which looks at the shape, size, and number of chromosomes in the body.[4] They will likely also conduct a test for testosterone levels.
Müllerian agenesis
If the sex chromosomes are XX, or normal female sex chromosomes, and the testosterone is within female range, then the diagnosis will be Müllerian agenesis, or Mayer-Rokitansky-Küster-Hauser syndrome.[5] Müllerian agenesis is caused by the underdevelopment of the Müllerian duct, or the part of the embryo that gives rise to the female reproductive tract. This results in the absence, failed development, or the closure of a duct in the vagina, uterus, or both.
Treatment for Müllerian agenesis includes, if the patient desires, the dilation of the vagina, whether through physical therapy or surgical means.[6] Those with this disorder may be unable to carry a pregnancy to term, even if fertile, and if that is the case, can rely on surrogacy or adoption to have children. They may benefit from psychological support, and must have routine gynaecological care. It is important to note that although patients with this disorder do not have a cervix and therefore are not at risk for cervical cancer, they should still receive the HPV vaccination.
One third of Müllerian agenesis cases also present with anomalies in the upper urinary tract, such as the malposition of an organ or renal agenesis. Ten to twenty percent of cases report skeletal abnormalities, most commonly involving vertebrae. These concerns will also be identified and treated with the Müllerian agenesis.[7]
Androgen insensitivity syndrome
If the sex chromosomes are XY, on the other hand, which are the male sex chromosomes, and the testosterone is within male range, then the diagnosis is either androgen insensitivity syndrome or 5-alpha reductase deficiency. They can be differentiated from each other by enzyme assays or genetic analysis.
Androgen insensitivity syndrome (AIS) is a group of X-linked genetic disorders of sexual development, where, despite being genetically male, the body does not respond to testosterone.[8] It can be complete AIS, where patients present with female genitalia, or partial AIS.
The treatment for complete AIS (as is often the case with amenorrhea) is hormone replacement therapy.[9] It almost always consists of an estrogen replacement because of the hormone’s role in bone health, the function of the cardiovascular system, and other essential bodily processes.[10] Progesterone may or may not be present as part of the treatment. Patients with complete AIS are generally infertile, and may therefore require psychological support and alternate options for having children.
5-alpha reductase deficiency
People with XY sex chromosomes and male-typical testosterone levels can also have abnormal development due to a deficiency in 5-alpha reductase, which affects sexual development from before birth.[11] They have male internal sexual organs, but their bodies do not produce enough dihydrotestosterone (DHT) to result in normal formation of external sex organs. This means most patients with this deficiency are assigned female at birth. However, during puberty, with an increase in male sex hormones, secondary sex characteristics follow the male pathway.
The primary goal of treating this condition is to align the external appearance of the patient with their gender identity. Hormone replacement therapy can assist the patient’s body in performing normally. Surgeries can reconstruct genitals to fit gender identity. 5-alpha reductase deficiency can be diagnosed at any point in the patient’s lifetime, and depending on the point at which it is diagnosed, psychological support may be necessary. As patients with this disorder are mostly infertile, they may require support to have children.
Presence of Uterus in Primary Amenorrhea
If the pelvic ultrasound results in establishing the presence of a uterus, then the follicle-stimulating hormone (FSH) and luteinising hormone (LH) levels are checked.
The female reproductive system works on what is called the hypothalamic-pituitary-ovarian axis pathway.[12] The hypothalamus, a part of the brain, produces gonadotrophin-releasing hormone (GnRH) at the onset of puberty. The GnRH then acts on the pituitary gland, an organ located at the base of the brain, which produces FSH and LH, which act on the ovaries to stimulate the production of estrogen and progesterone. If there is an issue with any stage of this process, then amenorrhea can occur.
Constitutional delay of growth and puberty
Low FSH and LH levels generally point to a constitutional delay of growth and puberty, which is a whole-body delay in the onset of puberty. Patients typically have a family history of so-called, ‘late bloomers,’ and when puberty begins, it continues as normal.[13] This can typically be diagnosed by checking the bone age through an X-ray, which will be delayed relative to normal.
Some conditions need to be ruled out to diagnose the constitutional delay. This disorder is typically identified by a shorter height relative to peers. However, there are other factors that can cause the same: their family is short and therefore there is a genetic cause for their height, they have a growth hormone deficiency, they are deficient in thyroid hormone (hypothyroidism), their body makes excess cortisol resulting in weight gain and decrease in height (Cushing syndrome), they have nutritional disorders, they were smaller than normal at birth, or they have genetic abnormalities in how their bones develop and grow (skeletal dysplasias).
Generally, the treatment is to wait and watch, as this disorder rarely points to something wrong with the patient.[14] Additionally, any hormonal treatments carry risks, as they could stimulate acceleration in skeletal growth and increase the risk of reduced final height. However, in worst-case scenarios, female patients may be prescribed with a limited dose of estradiol to stimulate breast development.
Functional hypothalamic amenorrhea
In some cases, low LH and FSH levels can indicate functional hypothalamic amenorrhea (FAH), which is caused by psychosocial stress, disordered or restrictive eating, and/or excessive exercise.[15] Although this typically presents in secondary amenorrhea, causing one third cases, if the unhealthy behaviours begin before menarche, it can cause primary amenorrhea as well. Ballet dancers and those in competitive sports are most at-risk.[16]
Increased stress levels results in the increase of corticotropin-releasing hormones and glucocorticoids such as cortisol. Disordered or restrictive eating, particularly anorexia nervosa and bulimia, as well as excessive exercise, limit the body’s energy supply. These factors suppress the hypothalamic-pituitary-ovarian axis pathway and ultimately affect the menstrual cycle.
Research on this condition is not comprehensive. Currently, treatments include addressing the root cause of the FAH, when it can be identified. There is also evidence to suggest the introduction of proteins such as kisspeptin may reduce symptoms.
Gonadotrophin-releasing hormone deficiency
Low LH and FSH levels can indicate a GnRH deficiency, as it means the pituitary gland never received instructions to produce LH and FSH.[17] It is a deficiency that, when combined with a lack of smell, is known as Kallman syndrome. Depending on the degree of the deficiency, there may be partial or complete failure of puberty, and infertility is highly likely. This condition is mostly congenital, or present from birth, but in some cases it can be idiopathic, indicating the cause is unknown.
Treatment includes hormone therapy, including estrogen and progesterone pills or patches.[18] The patient may also be injected with GnRH, to supplement the deficiency. In some cases, healthcare providers may prescribe Human Chorionic Gonadotropin (HCG) injections.
Outflow tract obstructions
If the FSH and LH levels are normal, the likely cause of amenorrhea is outflow tract obstruction, of which Müllerian agenesis and complete androgen insensitivity syndrome (IAS) are two types.[19] However, those two conditions can be easily identified in an ultrasound, while other types of outflow tract obstructions may not be as easily diagnosed.
This group of disorders also includes Asherman syndrome, or intrauterine synechiae, where scar tissue forms inside the uterus and cervix.[20] In a patient with primary amenorrhea, this is a very rare condition, and may be caused by infections such as schistosomiasis or tuberculosis. It can also be caused by surgical intervention on the organ. The treatment for this condition is surgical in nature, although experimental research in rebuilding the endometrium via the patient’s stem cells is ongoing and shows promise.
Outflow tract obstructions may also be caused by an imperforate hymen. The hymen is a small, thin membrane at the opening of the vagina which is formed by fragments of tissue left over during fetal development.[21] This tissue exists to protect the infant vagina from irritation, and rarely blocks the entire opening up to puberty. When it does, however, then it can block the outflow of menstruation, which can cause a lot of pain around the time of the patient’s first menstrual period. The treatment is a minor surgery.[22]
Similar to an imperforate hymen, the patient may have a transverse vaginal septum, or a “wall” of tissue that forms during development in the embryo, creating a blockage. This may be partial or complete, and will have similar symptoms to imperforate hymens. The treatment for the same is a surgical procedure.[23]
Primary ovarian insufficiency
Primary ovarian insufficiency, also known as premature ovarian insufficiency or failure, occurs when the ovaries cease functioning before age 40, and can be indicated by low FSH and LH levels.[24] This occurs when the ovaries don’t make the typical amounts of estogen or release eggs regularly, and leads to infertility.
Primary ovarian insufficiency differs from premature menopause because it is reversible.[25] Patients may get pregnant—between five and ten percent of women with primary ovarian insufficiency get pregnant after their diagnosis without significant medical intervention. Research suggests these women go into “spontaneous remission,” where their ovaries begin to function normally and their fertility is restored with no apparent cause. Often, their menstruation and uterine functioning returns to normal after their pregnancy.
The treatment for women with primary ovarian insufficiency is hormone replacement therapy. Estrogen and progestrone, along with testosterone in some cases, will be provided to the patient in order to restore normal sexual health function, supplementing the body with hormones the ovaries are not making. This also reduces the risk of cardiovascular disease, osteoporosis, and other such consequent disorders. With the hormones, the patient should begin having regular menstrual periods again.
Turner syndrome
If primary ovarian insufficiency is the diagnosis, the healthcare provider will likely conduct a karyotype analysis in order to rule of Turner syndrome. Turner syndrome is when one of the X chromosomes is missing, and results in delayed sexual development, a short stature, and other physical abnormalities including ear differences, a lower hairline, a small and receding jaw, and a short, wide neck, among others.[26]
Up to fifty percent of patients with Turner syndrome are born with a congenital heart condition that affects the structure of their heart. They may also have bone conditions, such as an increased risk of osteoporosis, fractures, and scoliosis, and autoimmune conditions, such as Celiac, Hashimoto’s thyroid disease, and inflammatory bowel disease. They might present with hearing and vision loss, kidney conditions, metabolic syndrome, and mental health challenges (including learning disabilities).
There is no cure for Turner syndrome, but the symptoms can be managed through hormone treatments. Growth hormone therapy, if started early, can help the patient achieve a higher final height. Estrogen hormone replacement therapy can help breast development and amenorrhea, as well as improving brain, heart, liver, and bone health. Healthcare providers may also induce menstruation through the use of cyclic progestins, which are medications with progesterone.
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