Discover causes, symptoms, and treatment options for Primary Amenorrhea, a condition affecting women who do not have their first menstrual period by age 16. Get valuable insights on Meri Sehat.

Primary Amenorrhea

Humza Khizer

Overview

Primary amenorrhea is defined as the failure to begin menstruation by age 13 in a girl with no secondary sexual characteristics. Or if a girl with secondary sexual characteristics has not begun menstruating by age 15.&nbsp;In females, puberty is associated with the onset of menstruation. It typically begins between the ages of 10 and 16 years. However, in some cases, menstruation may fail to begin. This is called primary amenorrhea. 
&nbsp;

The American College of Obstetricians and Gynecologists (ACOG) defines primary amenorrhea as the absence of periods by age 15<a href="#accordion">[5][6]</a>. Whereas, secondary amenorrhea is the absence of periods for 3 months or more in a woman who already menstruates.

The following cases should be evaluated for primary amenorrhea<a href="#accordion">[1]</a>:

<ul>
	<li>Absence of periods by 13 years of age in females with no secondary sexual characteristics (e.g., absence of breast development).</li>
	<li>Absence of periods in females aged 15 years or older with secondary sexual characteristics and normal growth. </li>
</ul>

&nbsp;

The prevalence of primary amenorrhea is less than 1% in the United States<a href="#accordion">[1]</a>. It usually results from anatomical defects, hormonal issues, and genetic problems. Gonadal dysgenesis, which includes Turner syndrome, accounts for 43% of cases<a href="#accordion">[1]</a>. Congenital malformation of the M&uuml;llerian ducts, including M&uuml;llerian agenesis, is another common cause of primary amenorrhea.

Recently, researchers in Peshawar, Pakistan conducted a cross-sectional study on cases of&nbsp; amenorrhea at a tertiary care hospital. Results showed that 60% of the cases had an anatomical defect<a href="#accordion">[7]</a>. Out of these, 7% had an imperforate hymen, 7% had a transverse vaginal septum, and 46% had Mullerian agenesis<a href="#accordion">[7]</a>.&nbsp;&nbsp; 
&nbsp;

Note: If you&rsquo;re 16 years old and have not yet started menstruating, contact a healthcare professional as it may be a sign of an underlying medical condition. 
&nbsp;

Primary amenorrhea has no further subtypes. 
&nbsp;

Signs and Symptoms

Amenorrhea is not a disease but rather a symptom. Primary amenorrhea can present with several other signs and symptoms, depending on the underlying cause. These include: 
&nbsp;

<ul>
	<li>Delayed puberty characterized by a lack of breast development or pubic hair growth.</li>
	<li>Absence of menstruation despite other puberty signs, such as breast development or pubic hair growth.</li>
	<li>Symptoms of hormonal imbalance, such as excessive facial hair growth, acne, or voice changes.</li>
	<li>Impaired or absent sense of smell (e.g., Kallmann syndrome)</li>
	<li>Chronic pelvic discomfort or pain.</li>
	<li>Perirectal mass due to accumulation of blood in the vagina.</li>
	<li>Short stature, webbed neck, low hairline, widely spaced nipples, high arched palate, multiple pigmented nevi, and short fourth metacarpal and metatarsals (e.g., Turner Syndrome).</li>
	<li>Absence of fallopian tubes, uterus, and the upper third of the vagina (e.g., complete androgen insensitivity syndrome).</li>
	<li>Inability to conceive or become pregnant.</li>
	<li>Low estrogen levels, as determined by blood tests. 
	&nbsp;</li>
</ul>

Causes

Anatomical defects, elevated follicle-stimulating hormone (FSH) levels, hyperprolactinemia, hypothalamic amenorrhea, or polycystic ovary syndrome cause the majority of cases of primary amenorrhea (<a href="https://merisehat.pk/disease/polycystic-ovary-syndrome-pcos">PCOS</a>).

Turner syndrome is the most common type of gonadal dysgenesis and accounts for 43% of primary amenorrhea cases<a href="#accordion">[1]</a>. 
&nbsp;

<h5>&nbsp;Anatomical Defects </h5>

<ul>
	<li>&nbsp;Mullerian Agenesis</li>
</ul>

Mayer-Rokitansky-K&uuml;ster-Hauser (MRKH) syndrome, another name for m&uuml;llerian agenesis, is a congenital malformation of the m&uuml;llerian ducts. It results in the absence of the uterus, and varying degrees of hypoplasia of the fallopian tubes, cervix, and first two-thirds of the vagina. It is the most common cause of primary amenorrhea, affecting about 1 in every 4,500 females<a href="#accordion">[2]</a>.&nbsp; 
&nbsp;

<ul>
	<li>Complete Androgen Insensitivity Syndrome</li>
</ul>

These individuals have a 46, XY karyotype and a defective androgen receptor. As a result, testosterone cannot activate cellular transcription. Therefore, the person will have female external genitalia. Moreover, m&uuml;llerian-derived structures, such as the fallopian tube, uterus, and upper part of the vagina will be absent.&nbsp;&nbsp;&nbsp; 
&nbsp;

<ul>
	<li>Transverse Vaginal Septum</li>
</ul>

A transverse vaginal septum is a birth defect in which a thin wall of tissue or membrane grows horizontally across the vagina, dividing it into two distinct sections. This tissue wall can partially or completely block the vaginal canal, making causing difficulty in the flow of menstrual blood&nbsp; and sexual intercourse<a href="#accordion">[3]</a>. 
&nbsp;

<ul>
	<li>Imperforate Hymen </li>
</ul>

Normally, a half-moon of thin membrane surrounds the opening of a young girl&#39;s vagina. A membrane extends all the way across the area of the hymen in the case of an imperforate hymen, blocking the vaginal opening. It is easily remedied with minor surgery. 
&nbsp;

<h5>Elevated FSH Levels</h5>

Elevated levels of the follicle-stimulating hormone (FSH) can indicate gonadal dysfunction. Gonadal failure refers to ovarian failure in people with XX chromosomes.&nbsp; 
&nbsp;

<h5>Hyperprolactinemia </h5>

Prolactin is a pituitary hormone that regulates a variety of reproductive functions. Prolactin secretion inhibits gonadotropin-releasing hormone secretion, which decreases the secretion of pituitary hormones. These hormones are responsible for gonadal function. 
&nbsp;

<h5>Hypothalamic Amenorrhea </h5>

This condition results in the cessation or absence of menstruation due to a functional disorder of the hypothalamus. 
&nbsp;

<h5>Polycystic Ovary Syndrome (PCOS)</h5>

Amenorrhea in females with androgen excess is most commonly caused by PCOS. It is a common endocrinologic and reproductive disorder. This syndrome is distinguished by three main features: hyperandrogenism, polycystic ovaries, and ovulatory dysfunction. Although it is a common cause of secondary amenorrhea, PCOS can also lead to primary amenorrhea. 

Amenorrhea can also be caused by hypopituitarism, weight loss, anorexia nervosa, and isolated gonadotropin-releasing hormone (GnRH) deficiency. Moreover,a genetic delay in puberty, as well as a chronic systemic disease or an acute illness can lead to primary amenorrhea. 
&nbsp;

The World Health Organization (WHO) divided amenorrhea into three categories:

<ul>
	<li>Females in WHO Group I have no evidence of endogenous estrogen production, normal or low follicle-stimulating hormone (FSH) levels, normal prolactin levels, and no evidence of hypothalamic-pituitary lesions. </li>
	<li>Females in WHO Group II can produce estrogen and have normal levels of prolactin and FSH.</li>
	<li>Females in WHO Group III have elevated serum FSH levels, indicating gonadal insufficiency or failure. 
	&nbsp;</li>
</ul>

There are no screening tests for primary amenorrhea. 
&nbsp;

Diagnosis

Evaluation of primary amenorrhea should begin three years after breast development in girls or within five years if breast development begins before the age of ten. A thorough personal medical history with height and weight charts, trends in height and weight development, nutritional status, and medications should be included in the evaluation of the adolescent with primary amenorrhea. It is important to rule out pregnancy in patients presenting with primary amenorrhea as ovulation occurs before the first period. 

In order to provide appropriate treatment and avoid potential complications, the underlying cause of primary amenorrhea must be determined. A thorough physical examination, medical history, and laboratory tests are used to diagnose primary amenorrhea. Some of the common diagnostic steps that a doctor may take are given below: 
&nbsp;

<ol>
	<li>
	<h5>Medical History</h5>
	</li>
</ol>

The doctor will inquire about the patient&#39;s menstrual history, including the age at which pubertal changes such as breast development began, and any previous or current medical conditions. Moreover, the doctor will inquire about symptoms such as cyclic abdominal pain, <a href="https://merisehat.pk/disease/anosmia">anosmia</a>, headaches, visual changes, or galactorrhea. 
&nbsp;

<ol start="2">
	<li>
	<h5>Physical Examination</h5>
	</li>
</ol>

A physical exam will be performed to look for signs of puberty, such as breast development and pubic hair. The healthcare provider will also look for any abnormalities in the abdomen, pelvis, and external genitalia. Furthermore, doctors will assess for signs and symptoms of Turner&rsquo;s syndrome, thyroid disorders, and gonadal dysgenesis. A rectal examination is also carried out to detect any hematocolpos. 
&nbsp;

<ol start="3">
	<li>
	<h5>Hormone Tests</h5>
	</li>
</ol>

Blood tests will be performed to determine hormone levels such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estrogen, progesterone, and testosterone. Hormone imbalances can reveal the underlying cause of primary amenorrhea. A pregnancy test is also conducted. 
&nbsp;

<ol start="4">
	<li>
	<h5>Imaging Studies</h5>
	</li>
</ol>

Ultrasound, MRI, or CT scans may be used to evaluate the reproductive organs and identify any structural abnormalities. 
&nbsp;

<ol start="5">
	<li>
	<h5>Chromosomal Analysis</h5>
	</li>
</ol>

This may be required in some cases to identify any genetic abnormalities that may be contributing to primary amenorrhea. 
&nbsp;

<ol start="6">
	<li>
	<h5>Other Specialized Tests</h5>
	</li>
</ol>

Additional specialized tests, such as hysteroscopy or laparoscopy, may be performed to assess the reproductive organs and detect any abnormalities.

Once the underlying cause of primary amenorrhea has been determined, treatment can begin. Depending on the causes, treatment may include hormonal therapy, surgery, or other interventions. It is critical to collaborate with a doctor to determine the best treatment plan. 
&nbsp;

Treatment

<h5>For the Treatment of Congenital Anomalies</h5>

<ol>
	<li>An imperforate hymen is treated with a cruciate lesion to open the vaginal orifice </li>
	<li>If a transverse septum is present, it must be surgically removed.</li>
	<li>In the presence of a functioning uterus, hypoplasia or absence of the cervix is more difficult to treat than other outflow obstructions. Cervical repair surgery is rarely successful, and a hysterectomy is usually required. By removing mature oocytes for in vitro fertilization and transferring embryos to a gestational carrier, the ovaries should be retained to provide the benefits of estrogen and to allow for the possibility of future childbearing.</li>
	<li>Progressive dilation is usually successful when the vagina is absent or short. 
	&nbsp;</li>
</ol>

<h5>Gonadal Treatment</h5>

For the initiation, maturation, and maintenance of secondary sexual characteristics in females with primary amenorrhea associated with all forms of gonadal failure and hypogonadotropic hypogonadism, cyclic estrogen and progestogen therapy is required.

<ol>
	<li>Therapy can begin with conjugated estrogens or estradiol once daily.</li>
	<li>Females with short stature should avoid high estrogen doses because they can cause the epiphyses to close prematurely.</li>
	<li>Unopposed estrogen stimulation of the endometrium can result in hyperplasia. To prevent hyperplasia, estrogen can be given daily in conjunction with progestogen.</li>
	<li>Patients with gonadal streaks and mosaicism may be able to ovulate and conceive either after starting estrogen therapy or on their own.</li>
	<li>If 17 alpha-hydroxylase deficiency is confirmed, treatment can begin with exogenous corticosteroid replacement therapy with hydrocortisone or dexamethasone. 
	&nbsp;</li>
</ol>

<h5>Therapeutic Measures</h5>

The primary cause of amenorrhea should be targeted with therapeutic measures. 
&nbsp;

<ol>
	<li>Craniopharyngiomas can be removed during craniotomy or through a transsphenoidal approach.</li>
	<li>Germinomas are extremely radiosensitive, so surgery is rarely recommended. </li>
	<li>Dopamine agonists may help with hyperprolactinemia and prolactinomas. </li>
	<li>Specific treatments can address underlying causes like anorexia nervosa or malnutrition.</li>
	<li>Individuals with Kallman syndrome or other causes of hypothalamic amenorrhea may benefit from hormone replacement therapy. 
	&nbsp;</li>
</ol>

If a female&#39;s karyotype contains the Y chromosome, as in gonadal dysgenesis, gonad removal is conducted to prevent the occurrence of tumors. 
&nbsp;

The causes of amenorrhea can also lead to other issues. These include: 
&nbsp;

<ul>
	<li><a href="https://merisehat.pk/disease/infertility-in-women">Infertility </a>And Problems With Pregnancy</li>
</ul>

Ovulation and menstruation are required for one to become pregnant. Without ovulation, there is no egg for the sperm to fertilize. When a hormone imbalance is the main cause of amenorrhea, it can also lead to miscarriage or other pregnancy complications. 
&nbsp;

<ul>
	<li>Psychological Stress</li>
</ul>

It can be stressful not to have periods when your squint does, especially for young people who are transitioning into adulthood. 
&nbsp;

<ul>
	<li><a href="https://merisehat.pk/disease/osteoporosis-80">Osteoporosis </a>And Cardiovascular Disease</li>
</ul>

These two issues can be caused by a lack of estrogen. Osteoporosis is a bone-weakening condition. Cardiovascular disease includes heart attacks as well as blood vessel and heart muscle problems. 
&nbsp;

<ul>
	<li>Pelvic Pain</li>
</ul>

If amenorrhea is caused by a structural defect, it may also cause pelvic pain. 
&nbsp;

The following factors can make one more susceptible to primary amenorrhea:

<ul>
	<li>Family history - A family history of genetic abnormalities, structural defects, or hormonal imbalances increases the risk of primary amenorrhea.</li>
	<li>Chromosomal abnormalities</li>
	<li>Structural defects</li>
	<li>Chronic illness 
	&nbsp;</li>
</ul>

There are no known preventive measures for primary amenorrhea. However, a healthy weight, regular physical activity, a balanced diet, regular gynecological visits, and treatment of underlying conditions can promote overall reproductive health.&nbsp; 
&nbsp;

Key Points

<ul>
	<li>The American College of Obstetricians and Gynecologists (ACOG) defines primary amenorrhea as the absence of periods by age 15. Whereas, secondary amenorrhea is the absence of periods for 3 months or more in a woman who already menstruates.</li>
	<li>Anatomical defects, elevated follicle-stimulating hormone (FSH) levels, hyperprolactinemia, hypothalamic amenorrhea, or polycystic ovary syndrome cause the majority of cases of primary amenorrhea (PCOS).</li>
	<li>Primary amenorrhea is diagnosed with a complete medical history and physical examination, imaging studies, blood-lab tests, and occasionally genetic testing.</li>
	<li>Depending on the underlying cause, hormone medication, surgery, or other medical procedures may be used as primary amenorrhea treatments.</li>
	<li>In rare instances, primary amenorrhea may not require treatment, but ongoing observation and care are necessary to guarantee general health and well-being. 
	&nbsp;</li>
</ul>

[1] Melnick A. Primary Amenorrhea. In: Problem-Focused Reproductive Endocrinology and Infertility. Springer; 2023. p. 25–31.

[2] on Adolescent Health Care C. Committee opinion no. 562: müllerian agenesis: diagnosis, management, and treatment. Obs Gynecol. 2013;121(5):1134–7.

[3] Gasner A, Rehman A. Primary Amenorrhea. 2020;

[4] Petrykowski JP, Calise AC, Doyle R, Hurd BJ, Doyle RA. An Atypical Cause of Primary Amenorrhea: A Case Report of Rare Vaginal Agenesis. Cureus J Med Sci. 2023;15(2).

[5] Lacroix AE, Gondal H, Shumway KR, et al. Physiology, Menarche. [Updated 2022 Mar 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.

[6] Amenorrhea: Absence of periods. ACOG.

[7] Bibi K, Azim P, Kifayatullah M, Shakeel F, Aamir M. Primary amenorrhea in females attending gynecological outpatient of a tertiary care hospital at Peshawar. Journal of the Pakistan Medical Association. 2020:1. doi:10.5455/jpma.24317.