Primary amenorrhea: causes, diagnosis, treatment and prognosis

Primary amenorrhea is the absence of the first menstruation by the age expected by current age norms. Current recommendations recommend screening if menarche has not occurred by age 15, as well as if more than three years have passed since the onset of breast development without the appearance of menstruation. If breast development has not occurred by age 13, this is a reason to investigate delayed puberty and the causes of primary amenorrhea before age 15. [1]

This is not an independent disease, but a clinical syndrome that can be associated with disturbances at any level of the hypothalamus-pituitary-ovarian-uterine-vagina-external tract axis. This is why primary amenorrhea can be combined with both the absence of puberty and normal breast development and a normal female appearance. Modern endocrinology and gynecology view it as a diagnostic challenge, where it is necessary not simply to "induce menstruation," but to find the mechanism that is preventing menstruation. [2]

A key feature of primary amenorrhea is that the same complaint can mask very different conditions. In one patient, the cause is Turner syndrome or another form of gonadal dysgenesis, in another, congenital absence of the uterus and upper vagina, in a third, outlet tract obstruction, in a fourth, central hypogonadism, and in a fifth, complete androgen insensitivity syndrome. Therefore, there is no universal "one-size-fits-all" test for this issue. [3]

From a practical standpoint, primary amenorrhea is important not only for reproductive function. It can be the first manifestation of a chromosomal disorder, chronic estrogen deficiency, bone and cardiovascular risks, congenital kidney anomalies, eating disorders, pituitary tumors, or disorders of sexual development. The earlier the cause is identified, the greater the chance of protecting bone tissue, ensuring normal sexual development, correcting anatomical problems, and properly discussing future fertility. [4]

According to current data, menarche occurs in approximately 98% of girls by age 15. Therefore, a wait-and-see approach after this age without examination is considered erroneous. Even if the patient feels well and has few other complaints, primary amenorrhea itself requires a systematic assessment. [5]

Code according to ICD-10 and ICD-11

In the International Classification of Diseases, 10th revision, primary amenorrhea has a separate code, N91.0 – primary amenorrhea. This is the most straightforward and clinically accurate code when the patient has not had a single spontaneous menstruation and the diagnosis is already formulated as primary amenorrhea. It is important to remember that this same section also contains separate codes for secondary and unspecified amenorrhea, so substituting codes reduces the accuracy of documentation. [6]

The International Classification of Diseases, 11th revision, also includes a special code, GA20.00, for primary amenorrhea. This reflects a modern approach in which primary amenorrhea is recognized as a distinct clinical category within menstrual disorders. If the cause has already been established, some coding systems further specify the underlying disorder, such as Turner syndrome, Mayer-Rokitansky-Küster-Hauser syndrome, or hypogonadism, but the basic amenorrhea code remains useful for describing the underlying syndrome. [7]

Below is a brief summary of the most relevant codes. [8]

Classification	Code	Meaning
ICD 10	N91.0	Primary amenorrhea
ICD 10	N91.1	Secondary amenorrhea
ICD 10	N91.2	Amenorrhea, unspecified
ICD 11	GA20.00	Primary amenorrhea
ICD 11	GA20.01	Secondary amenorrhea
ICD 11	GA20.0Z	Amenorrhea, unspecified

Epidemiology

Primary amenorrhea is significantly less common than secondary amenorrhea. Clinical literature estimates its prevalence in the general population at less than 0.1% in the United States, although older reviews also report ranges of 0.1-0.3%. This difference is explained by different definitions, the age of the patients included, and the fact that some cases are identified not in the general population but in specialized referrals. [9]

In gynecological clinics, the incidence is higher than in the general population. In a 2025 study from Pakistan, primary amenorrhea was 0.3% of 18,504 visits to a gynecological clinic. This does not mean that 0.3% of all girls will be diagnosed with this condition, but it does indicate that the problem is encountered regularly in specialized outpatient practices and requires a well-structured diagnostic pathway. [10]

The distribution of causes varies significantly depending on the clinic's level. In a 2025 study from southern Thailand, 46.9% of 320 patients were classified as eugonadal conditions, with Müllerian agenesis being the most common individual cause at 33.8%, followed by gonadal dysgenesis at 28.8%. In a 2024 American study, the distribution was different: hypergonadotropic hypogonadism accounted for 43%, hypogonadotropic hypogonadism for 31%, and eugonadal causes for 26%. This clearly demonstrates that the "most common cause" depends on the specialization of the center and who is referred there. [11]

Some individual conditions have their own epidemiology. Turner syndrome occurs in approximately 25-50 per 100,000 girls and women, Mayer-Rokitansky-Küster-Hauser syndrome occurs in approximately 1 per 4,000-5,000 girls, and imperforate hymen occurs in approximately 0.05-0.1% of girls. These numbers are important because these are the conditions often hidden behind the complaint of absent menstruation in adolescence.[12]

The age at diagnosis also depends on the cause. Outflow tract obstruction is usually diagnosed earlier, especially if cyclic pain develops rapidly. In contrast, Müllerian agenesis is often diagnosed later, sometimes in late adolescence or young adulthood, because puberty in these girls often appears normal. [13]

Below is a brief epidemiological summary.[14]

Indicator	What is known from modern data
Primary amenorrhea in the general population	Usually less than 0.1%, according to some reviews up to 0.1-0.3%
Frequency in one specialized gynecological clinic	0.3% of requests
Proportion of patients with eugonadal causes in the 2025 Thai series	46.9%
The most common single cause in the 2025 Thai series	Müllerian agenesis 33.8%
The next most common reason in the 2025 Thai series	Gonadal dysgenesis 28.8%
Distribution by cause type in the 2024 study	Hypergonadotropic hypogonadism 43%, hypogonadotropic 31%, eugonadal causes 26%
Turner syndrome	25-50 per 100,000 girls and women
Mayer-Rokitansky-Küster-Hauser syndrome	1 in 4,000-5,000 girls
Imperforate hymen	0.05-0.1%

Reasons

Current guidelines recommend considering the causes of primary amenorrhea based on three broad clinical questions: is there a uterus, are there breast development, and what is the hormonal profile? This approach is much more useful than a long, unsystematic list of diagnoses, because after an examination and the first ultrasound, the range of causes narrows dramatically. If a uterus is present but the breasts are not developing, hypogonadism is more often considered. If the breasts are developed but there is no uterus, the main options are Müllerian agenesis and complete androgen insensitivity syndrome. [15]

The first major group of causes is hypergonadotropic hypogonadism. Here, the problem lies at the level of the ovaries or gonads: they do not respond normally to stimulation, estrogen levels are low, and follicle-stimulating hormone levels are usually high. This group includes Turner syndrome, other forms of gonadal dysgenesis, some cases of premature ovarian failure, enzyme defects, and some genetic disorders. [16]

The second major group is hypogonadotropic hypogonadism. In this case, the problem is located higher up, in the hypothalamus or pituitary gland. Causes may include congenital gonadotropin-releasing hormone deficiency, congenital and acquired pituitary lesions, chronic energy deficiency, severe athletic activity, eating disorders, severe chronic diseases, hyperprolactinemia, and certain tumors of the central nervous system. [17]

The third group is eugonadal conditions with preserved estrogen production. These include congenital anomalies of the uterus and vagina, Müllerian agenesis, imperforate hymen, transverse vaginal septum, and other forms of vaginal outflow obstruction. In these situations, secondary sexual characteristics may be normal because the ovaries are functioning, but menstruation does not occur either because the uterus is absent or because the outflow of menstrual blood is blocked. [18]

Complete androgen insensitivity syndrome (CIS) occupies a special place. This rare condition, found in individuals with a 46,XY karyotype, is characterized by a female phenotype, breast development, and the absence of a uterus due to the action of anti-Müllerian hormone. In adolescence, the patient presents with a complaint of primary amenorrhea. It is characterized by the absence or marked sparseness of pubic and axillary hair, absence of a uterus, and testosterone levels that are either male or elevated in females. [19]

Another practical reason for delayed diagnosis is ultrasound error. In a 2025 Thai series of 44 patients with hypergonadotropic and hypogonadotropic hypogonadism, the uterus was not visualized on ultrasound, although the problem was not necessarily its actual absence, but sometimes severe hypoestrogenism and small size. This is a very important caveat: "not seeing the uterus" does not always mean Müllerian agenesis. [20]

Below is a practical diagram of the main reasons. [21]

Group of reasons	Examples	Typical tips
Hypergonadotropic hypogonadism	Turner syndrome, gonadal dysgenesis, ovarian failure	No or little estrogen, high levels of follicle-stimulating hormone
Hypogonadotropic hypogonadism	Congenital gonadotropin-releasing hormone deficiency, functional hypothalamic amenorrhea, pituitary causes	Low or "normal-low" gonadotropins and estrogen
Eugonadal anomalies	Mayer-Rokitansky-Küster-Hauser syndrome, imperforate hymen, vaginal septum	Normal secondary sexual characteristics, but no normal drainage or absent uterus
Disorders of sexual development	Complete androgen insensitivity syndrome, 46,XY gonadal dysgenesis	No uterus, hair growth characteristics, genetic and hormonal signs
Other endocrine causes	Hyperprolactinemia, thyroid disease	Changes in prolactin and thyroid-stimulating hormone
Rare genetic and enzyme defects	Receptor and enzymatic disorders	Require in-depth genetic evaluation

Risk factors

Risk factors for primary amenorrhea depend on its mechanism. For congenital forms, familial and genetic predisposition are paramount, although for many syndromes, the exact inheritance pattern is not always clear. This is especially important in familial cases of anomalies of sexual development, delayed puberty, mosaic forms of Turner syndrome, and in cases of suspected congenital hypogonadotropic hypogonadism. [22]

For hypothalamic forms, key risk factors include low energy availability, severe dietary restriction, weight loss, intense exercise, and eating disorders. In such cases, the body "scrimps" on reproductive function by suppressing normal secretion of gonadotropin-releasing hormone and reducing estrogen production. This is especially true for adolescents with a combination of thinness, high academic or athletic stress, and severe anxiety about body weight. [23]

Chronic conditions also increase the risk of primary amenorrhea. These include tumors and other pituitary lesions, severe systemic diseases, chronic inflammatory processes, and the effects of chemotherapy, radiation therapy, and ovarian surgery. The 2024 guidelines on female hypogonadism specifically emphasize that loss of ovarian function can occur as early as adolescence following cancer treatment. [24]

Specific causes have their own specific risk factors. In Mayer-Rokitansky-Küster-Hauser syndrome, congenital anomalies of the urinary system and spine are important, as the disease often falls within a broader syndrome spectrum. In Turner syndrome, chromosomal abnormalities are significant. In obstructive anomalies of the genital tract, the risk factor is essentially congenital, and the clinical trigger for detection is the onset of puberty. [25]

Below is a condensed table of risk factors.[26]

Risk factor	For what reasons is it especially important?
Family history of delayed puberty or infertility	Congenital hypogonadism, genetic forms
Low body weight and rapid weight loss	Functional hypothalamic amenorrhea
Intense sports and energy deficiency	Hypothalamic forms
Eating disorders	Central hypogonadism
Chemotherapy, radiation therapy, ovarian surgery	Ovarian insufficiency
Congenital anomalies of the kidneys and spine	Mayer-Rokitansky-Küster-Hauser syndrome, syndrome spectrum
Chromosomal abnormalities	Turner syndrome, gonadal dysgenesis
Tumors of the pituitary gland and central nervous system	Hypogonadotropic hypogonadism

Pathogenesis

The pathogenesis of primary amenorrhea is best understood through normal physiology. For menstruation to begin, all parts of the system must function: the hypothalamus must produce gonadotropin-releasing hormone, the pituitary gland must secrete follicle-stimulating and luteinizing hormones, the ovaries must produce estrogens and ensure follicle maturation, the uterus must have an endometrium capable of cyclical changes, and the uterine tract must be patent. A failure at any of these levels can lead to primary amenorrhea. [27]

If the damage occurs at the ovarian level, hypergonadotropic hypogonadism develops. The ovaries do not produce sufficient estrogen, and the pituitary gland "attempts" to stimulate them by increasing follicle-stimulating hormone, but there is no response. As a result, normal endometrial growth is not initiated, puberty does not develop fully or is incomplete, and bone tissue, the cardiovascular system, and the uterus are left without sufficient estrogen influence. [28]

If the problem is central, gonadotropin levels are low or abnormally normal, and estrogen production is reduced due to insufficient ovarian stimulation. This occurs with congenital gonadotropin-releasing hormone deficiency, pituitary gland damage, and functional hypothalamic amenorrhea. In such cases, the pathogenesis is often associated with energy deficiency, stress, or central organic damage, rather than a "failure" of the ovaries themselves. [29]

In Müllerian agenesis, the pathogenesis is different: the ovaries are usually normal, estrogen levels are sufficient, so the mammary glands develop, but the uterus and upper vagina are incompletely formed or absent. The menstrual cycle, as a hormonal process, may occur, but there is simply no bleeding. In obstructive anomalies, the opposite is true: the uterus is present and hormonal function is preserved, but bleeding cannot occur due to obstruction at the hymenal or vaginal level. [30]

In complete androgen insensitivity syndrome, the pathogenesis is associated with a mutation in the androgen receptor in individuals with a 46,XY karyotype. The testicles produce anti-Müllerian hormone, so the uterus does not develop, and androgens cannot exert their normal effects. Some testosterone aromatizes into estrogens, so the mammary glands often develop well, but menarche does not occur. [31]

Symptoms

The main symptom is the absence of the first menstruation by the age when examination is indicated. However, the clinical picture is rarely limited to this. It is the combination of amenorrhea with other signs that helps to understand the mechanism of the disease: for example, lack of breast development, cyclic pain, absence of a uterus on ultrasound, short stature, hair growth patterns, or signs of chronic energy deficiency. [32]

If a patient has normal breast development but no menstruation, the physician most often suspects uterine or vaginal tract anomalies. With an imperforate hymen and vaginal septum, cyclical lower abdominal pain, a feeling of pressure, sometimes urinary retention, and a mass due to the accumulation of menstrual blood are typical. In Mayer-Rokitansky-Küster-Hauser syndrome, the only complaint may be the absence of menstruation with a normal appearance and normal puberty. [33]

If the mammary glands do not develop or develop poorly, hypogonadism is often suspected. In such cases, growth retardation, absence of a growth spurt during puberty, sparse hair growth, dry mucous membranes, low bone mineral density, fatigue, hot flashes in some patients, as well as features of Turner syndrome, such as short stature, a broad chest, a history of lymphedema, or characteristic facial features, may be observed. [34]

In complete androgen insensitivity syndrome, the patient typically has a female phenotype and mammary glands, but noticeable features include sparse or absent pubic and axillary hair, the absence of a uterus, and sometimes the presence of inguinal lesions consistent with testicular tissue. This is why primary amenorrhea combined with normal mammary glands does not always indicate a normal 46,XX karyotype. [35]

Psychological symptoms should not be underestimated. For a teenager, the absence of menstruation often means anxiety, feelings of inferiority, fear of infertility, and social isolation. Current guidelines for Turner syndrome and Müllerian agenesis emphasize that psychosocial support should be integrated into diagnosis and treatment from the outset, rather than being introduced only after the diagnosis is made. [36]

Classification, forms and stages

From a clinical perspective, it's more convenient to divide primary amenorrhea not into "stages," but into forms based on hormonal and anatomical mechanisms. The most practical division includes hypergonadotropic hypogonadism, hypogonadotropic hypogonadism, eugonadal anatomical forms, and disorders of sexual development. This scheme is used in modern reviews and algorithms because it directly helps select further tests. [37]

A second useful classification method is based on two questions: whether a uterus is present and whether mammary glands are developing. If a uterus is present and mammary glands are developed, an outflow tract obstruction is most often sought. If a uterus is absent but mammary glands are present, the main options are Müllerian agenesis and complete androgen insensitivity syndrome. If a uterus is present but mammary glands are not developing, central and peripheral hypogonadism should be differentiated based on follicle-stimulating hormone and estradiol levels. [38]

Based on origin, congenital and acquired forms can be distinguished. Congenital forms predominate in gonadal dysgenesis, Mayer-Rokitansky-Küster-Hauser syndrome, congenital gonadotropin-releasing hormone deficiency, disorders of sexual development, and ovarian tract anomalies. Acquired causes are more common in patients who have undergone chemotherapy, radiation therapy, ovarian surgery, severe weight loss, and central tumors. [39]

There is no classical staging system for primary amenorrhea based on the type of cancer. However, in clinical practice, variants with delayed puberty, normal puberty and an anatomical cause, and disorders of sexual development are often distinguished. This helps both the physician and the family understand what to expect from the examination: hormonal correction, surgery, genetic counseling, or a combination of all these measures. [40]

Below is a practical classification. [41]

Criterion	Forms
By hormonal mechanism	Hypergonadotropic hypogonadism, hypogonadotropic hypogonadism, eugonadal forms
By anatomy	With uterus, without uterus, with obstruction of the outflow tract
By sexual development	With absence of puberty, with normal development of secondary characteristics, with disorder of sexual development
By origin	Congenital, acquired
Along the leading clinical path	Endocrine, anatomical, genetic, mixed

Complications and consequences

The main complication of primary amenorrhea is not the absence of bleeding itself, but the consequences of the underlying cause. With prolonged estrogen deficiency, bones, the formation of peak bone mass, the uterus, the cardiovascular system, and psychoemotional state are affected. This is especially important during adolescence, when the body must rapidly gain bone mass and complete puberty. [42]

Complications associated with obstruction of the vaginal outlet are different. If blood cannot be expelled, it can accumulate in the vagina and uterus, leading to severe cyclic pain, infectious complications, pressure on the urinary tract and intestines, and, in advanced cases, endometriosis-like complications due to retrograde blood flow. Therefore, an imperforate hymen and transverse vaginal septum require prompt surgical intervention rather than observation. [43]

With Turner syndrome and other forms of gonadal dysgenesis, the consequences extend far beyond the reproductive system. These can include short stature, aortopathy, hearing loss, autoimmune diseases, bone problems, and psychosocial adjustment. Therefore, a diagnosis of Turner syndrome cannot be simply "absence of menstruation"—it is a multisystemic condition. [44]

In the presence of Y-chromosomal material, the risk of gonadal tumors becomes a separate issue. Current guidelines indicate that in 46,XY gonadal dysgenesis or in Turner syndrome with Y-chromosomal material, the gonads should be removed due to the tumor risk. In complete androgen insensitivity syndrome, the issue is more complex: the tumor risk before puberty is low, so gonadectomy is often considered after spontaneous breast development has completed and adult height has been achieved. [45]

Finally, the most important consequence remains the impact on fertility and body image. For some reasons, spontaneous or induced ovulation and pregnancy are possible; for others, pregnancy is only possible with donor eggs, surrogacy programs where they are legal, or after complex reconstructive and experimental approaches such as uterine transplantation. Therefore, the conversation about future motherhood should be honest, early, and personalized. [46]

Below is a summary of the main consequences.[47]

Group of complications	What could be happening?
Bone	Decreased peak bone mass accumulation, risk of osteopenia and osteoporosis
Reproductive	Infertility, decreased ovarian reserve, need for assisted reproductive technologies
Anatomical	Hematocolpos, pain, endometriosis-like complications with obstruction
Oncological	Risk of gonadal tumors in the presence of Y-chromosomal material
Psychological	Anxiety, depression, body image disorders, social isolation
Systemic	Cardiovascular, renal, auditory and other complications in syndromic forms

When to see a doctor

An examination is mandatory if menarche has not occurred by age 15, if more than 3 years have passed since the onset of breast development without the onset of menstruation, and if breast development has not occurred by age 13. This is not a "late individual norm," but an accepted threshold beyond which the cause should be sought. [48]

Urgent medical attention is required if the absence of menstruation is accompanied by cyclical lower abdominal pain, abdominal distension, urinary retention, severe headaches, visual impairment, significant weight loss, symptoms of an eating disorder, inguinal masses, or a family history of chromosomal or genetic conditions. These symptoms may indicate an obstruction, a pituitary tumor, central hypogonadism, or a disorder of sexual development. [49]

It's also important not to delay a visit because early diagnosis impacts growth, bone formation, and future fertility. In some conditions, treatment initiated early allows for a more natural puberty induction, improved uterine size, stronger bones, and an early discussion of reproductive strategies. [50]

Diagnostics

Diagnosis begins with a detailed interview. The doctor will determine the age of onset of thelarche, growth rate, weight changes, physical activity, diet, stress, chronic illnesses, surgeries, chemotherapy, family history of late puberty, as well as cyclical pain and sexual development patterns. The American Society for Reproductive Medicine emphasizes that a medical history, physical examination, and baseline hormonal profile can identify most causes. [51]

The next step is an examination. This should include an assessment of growth, body proportions, stage of sexual development, condition of the external genitalia, presence or absence of hair, signs of Turner syndrome, and signs of hypoestrogenism. A physical examination is especially valuable in cases of primary amenorrhea, because the combination of the uterus, mammary glands, and external phenotype often narrows the range of causes. [52]

A basic laboratory kit typically includes a pregnancy test, follicle-stimulating hormone, luteinizing hormone, estradiol, prolactin, and thyroid-stimulating hormone. Pregnancy is rare, but it should always be ruled out if anatomically possible. Based on follicle-stimulating hormone and estradiol levels, the doctor differentiates between central and peripheral hypogonadism, while prolactin and thyroid-stimulating hormone help detect hyperprolactinemia and thyroid disease. [53]

The instrumental basis for diagnosis is a pelvic ultrasound. It helps determine the presence of a uterus, the appearance of the ovaries, signs of blood accumulation due to obstruction, and the presence of tumor changes. However, it is important to remember a diagnostic pitfall: in patients with severe hypoestrogenicity, a small uterus may be poorly visualized, so a questionable ultrasound result cannot be automatically interpreted as the absence of a uterus. [54]

If the uterus is absent or complex anomalies are suspected, the next steps are often karyotyping and testosterone measurement. These two tests help differentiate between Mayer-Rokitansky-Küster-Hauser syndrome and complete androgen insensitivity syndrome. If Turner syndrome is suspected, a karyotype with a sufficient number of metaphases is needed, and if clinical signs of a central cause are present, magnetic resonance imaging of the pituitary gland and brain may be indicated. [55]

Further testing depends on the initial diagnosis. This may include anti-Müllerian hormone, free and total testosterone, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, genetic panels, bone age, densitometry, kidney and spine assessment in Mayer-Rokitansky-Küster-Hauser syndrome, and an in-depth cardiac evaluation in Turner syndrome. Modern diagnostics should be step-by-step: not a chaotic set of tests, but a logical progression from phenotype to mechanism. [56]

Below is a simplified algorithm. [57]

Step	What are they doing?	What does this give?
1	Detailed anamnesis	Helps to identify central, anatomical, genetic and energetic causes
2	Examination and stage of sexual development	Shows whether there is a delay in puberty and signs of syndromic conditions
3	Pregnancy test	Eliminates a rare but necessary option
4	Follicle-stimulating hormone, luteinizing hormone, estradiol	Distinguishes between hypergonadotropic and hypogonadotropic variants
5	Prolactin and thyroid-stimulating hormone	Identifies common endocrine causes
6	Ultrasound examination of the pelvis	Allows assessment of the uterus, ovaries and obstruction
7	Karyotype and testosterone	Particularly important in the absence of a uterus or suspected gonadal dysgenesis
8	Magnetic resonance imaging and genetics as indicated	Needed for central and complex genetic forms

Differential diagnosis

In the differential diagnosis of primary amenorrhea, the most important thing is not to confuse the absence of the uterus with a very small, hypoestrogenic uterus. This error can lead to a false diagnosis of Mayer-Rokitansky-Küster-Hauser syndrome in a patient with central or peripheral hypogonadism. A 2025 Thai study specifically warns of this, as in hypoestrogenic states, the uterus may not be visible on ultrasound. [58]

The second key distinction is between Mayer-Rokitansky-Küster-Hauser syndrome and complete androgen insensitivity syndrome. In both cases, the uterus may be absent and the vagina may be short, but in complete androgen insensitivity syndrome, the karyotype is 46,XY, testosterone levels are in the male range or above the female range, and pubic and axillary hair is usually sparse. In Müllerian agenesis, the karyotype is 46,XX and the ovaries are usually normal. [59]

The third important task is to distinguish hypergonadotropic hypogonadism from hypogonadotropic hypogonadism. In the former, follicle-stimulating hormone levels are high because the ovaries are unresponsive. In the latter, they are low or abnormally normal because of insufficient stimulation from above. Clinically, this distinction is crucial: in the central forms, one can look for energy deficiency, hyperprolactinemia, or pituitary damage, while in the peripheral forms, one can look for Turner syndrome, gonadal dysgenesis, or ovarian failure. [60]

Finally, it's important to distinguish between anatomical obstruction and the absence of the uterus itself. With an imperforate hymen and vaginal septum, the patient often experiences cyclic pain and blood accumulation, whereas with Müllerian agenesis, menstrual blood usually does not form due to the absence of a fully functional uterus. This distinction has direct therapeutic implications: in one case, surgery to restore outflow is necessary, while in the other, consideration should be given to vaginal dilation, reproductive options, and a syndromic search. [61]

Below is a brief comparison table. [62]

State	Uterus	Mammary glands	Key differences
Mayer-Rokitansky-Küster-Hauser syndrome	None or severely underdeveloped	Usually developed	Karyotype 46,XX, normal ovaries
Complete androgen insensitivity syndrome	No	Usually developed	Karyotype 46,XY, sparse hair growth, high testosterone
Turner syndrome and gonadal dysgenesis	Usually there is, but it can be small	Often underdeveloped	High follicle-stimulating hormone, chromosomal changes
Central hypogonadism	Usually there is, but it's small.	Underdeveloped or delayed	Low or inadequately normal gonadotropins
Imperforate hymen	Eat	Developed	Cyclic pain, hematocolpos
Transverse vaginal septum	Eat	Developed	Obstruction, pain, outflow tract obstruction

Treatment

Treatment of primary amenorrhea should always be cause-based. Current guidelines emphasize that "inducing menstruation" alone, without understanding the underlying mechanism, is an inappropriate strategy. Therapeutic goals include not only the appearance of bleeding, but also normal sexual development, bone protection, prevention of cardiovascular and psychosocial complications, and consideration of future fertility. [63]

If the cause is related to estrogen deficiency in hypogonadism, puberty induction with estradiol becomes the mainstay of treatment. Internationally, 17-beta-estradiol is increasingly preferred, with doses increased gradually, mimicking the natural pace of puberty. The 2022 puberty induction guidelines recommend continuing this process over 2-4 years until reaching the adult replacement dose, rather than attempting to accelerate puberty in a few months. [64]

For girls and adolescents with Turner syndrome, current guidelines from 2024 recommend initiating low-dose estrogen therapy at approximately 11–12 years of age if follicle-stimulating hormone levels are persistently elevated on at least two consecutive measurements. The dose is increased slowly over two to four years. 17-beta-estradiol is considered the preferred physiological form because it better matches the normal estrogen profile and is associated with good bone health and uterine growth. [65]

When a patient has a uterus and estrogen therapy has already caused significant endometrial development, a progestogen is added to the treatment to protect the endometrium and promote cyclical bleeding. Prescribing a progestogen too early is undesirable because it can interfere with the proper development of the uterus and mammary glands. Modern regimens emphasize the correct sequence: first gradual estrogenization, then progestogen. [66]

In hypothalamic forms of treatment, hormones alone are often insufficient. If primary amenorrhea is associated with energy deficiency, an eating disorder, or excessive physical activity, the central goal is to restore energy availability, body weight, diet, sleep, and reduce stress. In cases of persistent hypoestrogenism, physiological hormonal replacement is also considered, as prolonged delays without correction worsen bone and reproductive health. [67]

If the cause is central, but not functional, but rather a congenital gonadotropin-releasing hormone deficiency or pituitary insufficiency, treatment is more specialized. Estradiol is used to induce puberty, and if future pregnancy is planned, pulsed gonadotropin-releasing hormone therapy or gonadotropins for ovulation induction are possible. Current data confirm that in congenital hypogonadotropic hypogonadism, such methods remain the primary means of restoring fertility. [68]

In cases of imperforate hymen, vaginal septum, and other obstructive anomalies, treatment is surgical. The goal of the surgery is to ensure adequate drainage, eliminate pain, prevent recurrent blood accumulation, and reduce the risk of complications for the uterus, fallopian tubes, and pelvis. In published clinical series, such patients were treated with hymenotomy, septal excision, and other reconstructive procedures depending on the level of the obstruction. [69]

For Mayer-Rokitansky-Küster-Hauser syndrome, treatment must be very delicate and phased. The first line of treatment is not surgery, but vaginal dilation after detailed counseling, as it yields a high percentage of functional results with a lower risk of complications. Surgical creation of a neovagina is considered a second step if dilation is unsuccessful, unacceptable for the patient, or anatomically impossible. Concurrent examinations of the kidneys, spine, hearing, and, if necessary, the heart are mandatory, as some patients have a syndromic variant of the disease. [70]

For complete androgen insensitivity syndrome, treatment includes genetic and psychosocial counseling, discussion of the timing of gonadectomy, and subsequent hormonal replacement. Current reviews and systematic data indicate that the risk of malignant changes before puberty is low, so gonadectomy is often delayed until spontaneous breast development is complete. After gonadectomy, estrogen replacement therapy is required to maintain bone, sexual health, and overall well-being. [71]

For 46,XY gonadal dysgenesis and Turner syndrome with Y-chromosomal material, the approach is different. Here, the risk of gonadal tumors is higher, and recommendations favor earlier removal of the dysgenetic gonads. After this, the patient requires individually tailored hormone replacement and long-term monitoring. This is one example where a similar-looking complaint of primary amenorrhea leads to fundamentally different surgical tactics depending on the genetic diagnosis. [72]

New treatments focus primarily on reproductive options, not amenorrhea syndrome itself. For Mayer-Rokitansky-Küster-Hauser syndrome, specialized centers are discussing surrogacy programs where they are legal, and uterine transplantation is a developing approach. These approaches cannot yet be considered standard for everyone, but they have changed the reproductive prognosis for some patients. At the same time, for adolescents with expected loss of ovarian function, early counseling on fertility preservation and long-term planning are becoming increasingly important. [73]

Below is a summary table of treatments.[74]

Cause	The basic approach
Turner syndrome and gonadal dysgenesis	Low-dose 17-beta-estradiol with gradual increase, later progestogen if the uterus is present
Central hypogonadism	Treatment of the cause, induction of puberty with estradiol, when planning pregnancy - gonadotropins or pulsatile gonadotropin-releasing hormone
Functional hypothalamic amenorrhea	Restoration of nutrition, body weight, reduction of excessive stress, psychotherapeutic support, and, if indicated, hormonal replacement
Imperforate hymen	Surgical restoration of outflow
Transverse vaginal septum	Surgical excision and reconstruction
Mayer-Rokitansky-Küster-Hauser syndrome	The first line is vaginal dilation, the second is reconstructive surgery
Complete androgen insensitivity syndrome	Individual discussion of the timing of gonadectomy, followed by estrogen replacement
Dysgenetic gonads with Y-material	Gonadectomy due to tumor risk, then hormonal therapy

Prevention

Not all causes of primary amenorrhea can be prevented, as a significant portion are congenital or genetic. Turner syndrome, Müllerian agenesis, or congenital gonadal dysgenesis cannot be "prevented" with routine behavioral measures. However, late diagnosis can be prevented, and for adolescents, this is often no less important than preventing the underlying cause. [75]

Effective preventative measures primarily address functional hypothalamic disorders. Adequate nutrition, the absence of chronic energy deficiency, caution during intense exercise, timely treatment for eating disorders, and monitoring of growth and puberty dynamics significantly reduce the risk of hormonal problems being detected too late. [76]

Educational prevention is also very important. Adolescents, parents, and primary care physicians should be aware that the absence of menstruation by age 15 or more than three years after the onset of breast development is not considered normal. The earlier the screening process is initiated, the lower the risk of missing the opportunity for proper pubertal induction, bone protection, and correction of the underlying anatomical cause. [77]

For patients with known genetic and syndromic conditions, prevention essentially means pre-arranged monitoring. In Turner syndrome and congenital hypogonadism, monitoring should begin even before the expected age of menarche, so that the transition to hormonal therapy is timely, rather than delayed and reactive. [78]

Forecast

The prognosis for primary amenorrhea depends not on the absence of menstruation itself, but on the cause, age at diagnosis, and quality of treatment. With obstructive anomalies of the cervical outflow tract, the prognosis is usually good after timely surgery: pain disappears, outflow is restored, and fertility may be preserved in some patients. With functional hypothalamic forms, the prognosis can also be favorable if energy balance is restored and prolonged hypoestrogenism is avoided. [79]

In hypogonadism, the prognosis largely depends on how early puberty induction is initiated. Current data show that timely administration of 17-beta-estradiol and gradual dose increases are associated with improved chances of normal breast development, more adequate uterine growth, and improved bone mass accumulation. Delaying treatment worsens these parameters and makes recovery less physiological. [80]

The reproductive prognosis varies greatly. In central hypogonadism, ovulation induction and pregnancy are possible. In Mayer-Rokitansky-Küster-Hauser syndrome, the ovaries are usually functional, so biological motherhood can be considered through assisted reproduction programs, and in some centers, even through uterine transplantation. In severe gonadal dysgenesis and severe ovarian failure, the prospects for a natural genetic pregnancy are much more limited and often require donor oocytes or other parenting options. [81]

The psychosocial prognosis is also important. Even with a good medical outcome, primary amenorrhea can leave a lasting impact on self-esteem and sexual identity. Therefore, a good modern prognosis depends not only on the occurrence of bleeding or a technically successful surgery, but also on quality support, a clear explanation of the diagnosis, addressing anxiety, and a realistic discussion of fertility. [82]

Below is a brief summary of prognostic factors.[83]

Factor	How does it affect the prognosis?
Early diagnosis	Improves bone, sexual and psychological outcomes
Timely induction of puberty	Improves the development of the uterus, bone tissue and secondary characteristics
Anatomically remediable cause	Usually gives a more favorable functional prognosis
Severe gonadal insufficiency	Limits spontaneous fertility
Presence of the uterus and intact ovaries	Improves reproductive prospects
Syndromic forms	Require long-term interdisciplinary observation
Psychosocial support	Improves quality of life and adherence to treatment

FAQ

What is considered primary amenorrhea by modern criteria?
The absence of menarche by age 15, the absence of menstruation for more than 3 years after the onset of breast development, and the absence of breast development by age 13, at which point one should look for delayed puberty. [84]

Does primary amenorrhea always mean infertility?
No. It all depends on the cause. In central forms and some anatomical conditions, pregnancy may be possible after treatment. In Mayer-Rokitansky-Küster-Hauser syndrome, biological motherhood is theoretically possible with intact ovaries through assisted reproductive technologies, and in some forms of hypogonadism, ovulation can be induced. [85]

If the mammary glands have developed normally, is the cause necessarily not hormonal?
No. Normal mammary gland development suggests that estrogen exposure has already occurred, but does not exclude a number of conditions, including Müllerian agenesis, complete androgen insensitivity syndrome, and some eugonadal variants. [86]

Can ultrasound falsely indicate the absence of the uterus?
Yes. In severely hypoestrogenic patients, the uterus may be very small and poorly visualized. Therefore, questionable results require re-evaluation and comparison with hormonal data, and sometimes additional imaging techniques. [87]

Should everyone have genetic testing?
Not everyone, but in cases of uterine insufficiency, suspected Turner syndrome, disorders of sexual development, gonadal dysgenesis, and complex cases, karyotyping is often a key step. [88]

What is the current treatment for puberty induction?
Gradual administration of 17-beta-estradiol with a slow increase in dose over 2-4 years, followed by the addition of a progestogen if the uterus is present and the endometrium is already under the influence of estrogens. [89]

What to do for Mayer-Rokitansky-Küster-Hauser syndrome?
The first line is vaginal dilation after proper counseling. Surgery is considered as a second step if conservative treatment is ineffective or ineffective. The kidneys and other possible associated abnormalities are also examined simultaneously. [90]

When are gonads removed in complete androgen insensitivity syndrome?
Many modern approaches consider gonadectomy after puberty, as the risk of malignant changes before puberty is low, and the patient's own gonads ensure spontaneous mammary gland development. However, the decision is always made individually and after confirmation of the diagnosis. [91]

Key points from experts

Channa N. Jayasena, MD, Professor of Reproductive Endocrinology and Andrology at Imperial College London and Consultant in Reproductive Endocrinology at Hammersmith Hospital and St Mary's Hospital, is a professor of reproductive endocrinology at the University of Cambridge. His key practical message for primary amenorrhea is that estrogen deficiency in adolescents should be considered not only as a menstrual issue but also as a bone, cardiovascular, and reproductive health issue. Therefore, hormonal therapy should be physiological, stepwise, and integrated into long-term follow-up. [92]

Claus Højbjerg Gravholt, MD, Clinical Professor and Consultant in the Department of Endocrinology and Internal Medicine at Aarhus University Hospital. His work in international guidelines on Turner syndrome emphasizes that patients with primary amenorrhea should not be treated "in a vacuum." If the cause is chromosomal, the evaluation should include not only hormonal assessments but also cardiovascular, renal, skeletal, and psychosocial monitoring, and pubertal induction should begin promptly, usually at 11–12 years of age if ovarian insufficiency is confirmed. [93]

Katherine O'Flynn O'Brien, MD, a board-certified obstetrician/gynecologist specializing in pediatric and adolescent gynecology at Children's Minnesota, is a key practitioner. The current clinical implications of her group's work are that the landscape of primary amenorrhea is changing, and diagnosis needs to be faster and more accurate than in the past. Of particular importance are early pelvic imaging, hormonal profiling, and caution in interpreting an "absent uterus" on the initial ultrasound. [94]

Conclusion

Primary amenorrhea is not a rare "cycle peculiarity," but an important clinical sign requiring a step-by-step assessment. Modern examination criteria are simple: absence of menarche by age 15, more than 3 years after the onset of breast development without menstruation, or the absence of signs of puberty by age 13. Following this, the physician should consistently answer questions about the presence of a uterus, the degree of development of secondary sexual characteristics, and the patient's hormonal profile. [95]

The most common causes fall into three broad groups: central hypogonadism, ovarian failure or gonadal dysgenesis, and anatomical abnormalities of the uterus, vagina, and ovarian tract. Modern treatment is also always causal: from gradual pubertal induction with 17-beta-estradiol to surgical correction of obstruction, non-invasive dilation in Mayer-Rokitansky-Küster-Hauser syndrome, and genetically based tactics for disorders of sexual development. [96]

The key practical point is that timely diagnosis impacts more than just menstruation. It also determines growth, bone mass, sexual development, mental well-being, and future fertility. Therefore, primary amenorrhea is a situation where early referral to a pediatric gynecologist, endocrinologist, and, if necessary, a geneticist can truly change the long-term outcome. [97]