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Amenorrhea is the absence of a
menstrual period The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs ...
in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...
and
lactation Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The proces ...
(
breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...
). Outside the reproductive years, there is absence of menses during childhood and after
menopause Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
. Amenorrhoea is a symptom with many potential causes. Primary amenorrhea is defined as an absence of
secondary sexual characteristics Secondary sex characteristics are features that appear during puberty in humans, and at sexual maturity in other animals. These characteristics are particularly evident in the sexually dimorphic phenotypic traits that distinguish the sexes of a ...
by age 13 with no
menarche Menarche ( ; ) is the first menstrual cycle, or first menstrual bleeding, in female humans. From both social and medical perspectives, it is often considered the central event of female puberty, as it signals the possibility of fertility. Gir ...
or normal secondary sexual characteristics but no menarche by 15 years of age. It may be caused by developmental problems, such as the congenital absence of the uterus, failure of the
ovary The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. ...
to receive or maintain
egg cells The egg cell, or ovum (plural ova), is the female reproductive cell, or gamete, in most anisogamous organisms (organisms that reproduce sexually with a larger, female gamete and a smaller, male one). The term is used when the female gamete is ...
, or delay in pubertal development. Secondary amenorrhoea, ceasing of menstrual cycles after menarche, is defined as the absence of menses for three months in a woman with previously normal menstruation, or six months for women with a history of oligomenorrhoea. It is often caused by hormonal disturbances from the
hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus ...
and the
pituitary gland In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The h ...
, premature
menopause Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often d ...
, intrauterine scar formation, or eating disorders.


Pathophysiology

Although amenorrhea has multiple potential causes, ultimately, it is the result of hormonal imbalance or an anatomical abnormality. Physiologically, menstruation is controlled by the release of
gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released ...
(GnRH) from the hypothalamus. GnRH acts on the pituitary to stimulate the release of
follicle stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, a ...
(FSH) and
luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...
(LH). FSH and LH then act on the ovaries to stimulate the production of estrogen and progesterone which, respectively, control the proliferative and secretary phases of the
menstrual cycle The menstrual cycle is a series of natural changes in hormone production and the structures of the uterus and ovaries of the female reproductive system that make pregnancy possible. The ovarian cycle controls the production and release of eggs ...
. Prolactin also influences the menstrual cycle as it suppresses the release of LH and FSH form the pituitary. Similarly, thyroid hormone also affects the menstrual cycle. Low levels of thyroid hormone stimulate the release of TRH from the hypothalamus, which in turn increases both TSH and prolactin release. This increase in prolactin suppresses the release of LH and FSH through a negative feedback mechanism. Amenorrhea can be caused by any mechanism that disrupts this hypothalamic-pituitary-ovarian axis, whether that it be by hormonal imbalance or by disruption of feedback mechanisms.


Classification

Amenorrhea is classified as either primary or secondary.


Primary Amenorrhea

Primary amenorrhoea is the absence of menstruation in a woman by the age of 16. Females who have not reached menarche at 14 and who have no signs of secondary sexual characteristics ( thelarche or pubarche) are also considered to have primary amenorrhea. Examples of amenorrhea include constitutional delay of puberty, Turner syndrome, and Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome.


Secondary Amenorrhea

Secondary amenorrhoea is defined as the absence of menstruation for three months in a woman with a history of regular cyclic bleeding or six months in a woman with a history of irregular menstrual periods. Examples of secondary amenorrhea include hypothyroidism, hyperthyroidism, hyperprolactinemia, polycystic ovarian syndrome, primary ovarian insufficiency, and functional hypothalamic amenorrhea.


Causes


Primary amenorrhea


Turner syndrome

Turner syndrome Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low h ...
, monosomy 45XO, is a genetic disorder characterized by a missing, or partially missing, X chromosome. Turner syndrome is associated with a wide spectrum of features that vary with each case. However, one common feature of this syndrome is ovarian insufficiency due to gonadal dysgenesis. Most people with Turner syndrome experience ovarian insufficiency within the first few years of life, prior to menarche. Therefore, most patients with Turner syndrome will have primary amenorrhea. However, the incidence of spontaneous puberty varies between 8–40% depending on whether or not there is a complete or partial absence of the X chromosome.


MRKH

MRKH (Mayer–Rokitansky–Küster–Hauser) syndrome is the second-most common cause of primary amenorrhoea. The syndrome is characterized by
Müllerian agenesis Müllerian agenesis, also known as Müllerian aplasia, vaginal agenesis, or Mayer-Rokitansky-Küster-Hauser syndrome (MRKH syndrome), is a congenital malformation characterized by a failure of the Müllerian ducts to develop, resulting in a miss ...
. In MRKH Syndrome, the Müllerian ducts develop abnormally and result in the absence of a uterus and cervix. Even though patient's with MRKH have functioning ovaries, and therefore have secondary sexual characteristics, they experience primary amenorrhea since there is no functioning uterus.


Constitutional delay of puberty

Constitutional delay of puberty is a diagnosis of exclusion that is made when the workup for primary amenorrhea does not reveal another cause. Constitutional delay of puberty is not due to a pathologic cause. It is considered a variant of the timeline of puberty. Although more common in boys, girls with delayed puberty present with onset of secondary sexual characteristics after the age of 14, as well as menarche after the age of 16. This may be due to genetics, as some cases of constitutional delay of puberty are familial.


Secondary amenorrhea


Breastfeeding

Physiologic amenorrhea is present before menarche, during pregnancy and breastfeeding, and after menopause. Breastfeeding or lactational amenorrhea is also a common cause of secondary amenorrhoea. Lactational amenorrhea is due to the presence of elevated prolactin and low levels of LH, which suppress ovarian hormone secretion. Breastfeeding typically prolongs postpartum lactational amenorrhoea, and the duration of amenorrhoea varies depending on how often a woman breastfeeds. Due to this reason, breastfeeding has been advocated as a method of family planning, especially in developing countries where access to other methods of contraception may be limited.


Diseases of the thyroid

Disturbances in thyroid hormone regulation has been a known cause of menstrual irregularities, including secondary amenorrhea. Patients with
hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as ...
frequently present with changes in their menstrual cycle. It is hypothesized that this is due to increased TRH, which goes on to stimulate the release of both TSH and prolactin. Increased prolactin inhibits the release of LH and FSH which are needed for ovulation to occur. Patients with
hyperthyroidism Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidis ...
may also present with oligomenorrhea or amenorrhea. Sex hormone binding globulin is increased in hyperthyroid states. This, in turn, increases the total levels of
testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
and
estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...
. Increased levels of LH and FSH have also been reported in patients with hyperthyroidism.


Hypothalamic and pituitary causes

Changes in the hypothalamic-pituitary axis is a common cause of secondary amenorrhea. GnRH is released from the hypothalamus and stimulates the anterior pituitary to release FSH and LH, which in turn stimulate the ovaries to release estrogen and progesterone. Any pathology in the hypothalamus or pituitary can alter the way this feedback mechanism works and can cause secondary amenorrhea. Pituitary adenomas are a common cause of amenorrhea. Prolactin secreting pituitary adenomas cause amenorrhea due to the hyper-secretion of prolactin which inhibits FSH and LH release. Other space occupying pituitary lesions can also cause amenorrhea due to the inhibition of dopamine, an inhibitor of prolactin, due to compression of the pituitary gland.


Polycystic ovary syndrome

Polycystic ovary syndrome Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...
(PCOS) is a common endocrine disorder affecting 4–8% of women worldwide. It is characterized by multiple cysts on the ovary, amenorrhea or oligomenorrhea, and increased androgens. Although the exact cause remains unknown, it is hypothesized that increased levels of circulating androgens is what results in secondary amenorrhea. PCOS may also be a cause of primary amenorrhea if androgen access is present prior to menarche. Although multiple cysts on the ovary are characteristic of the syndrome, this has not been noted to be a cause of the disease.


Low body weight

Women who perform extraneous exercise on a regular basis or lose a significant amount of weight are at risk of developing hypothalamic amenorrhoea. Functional hypothalamic amenorrhoea (FHA) can be caused by stress, weight loss, or excessive exercise. Many women who diet or who exercise at a high level do not take in enough calories to maintain their normal menstrual cycles. The threshold of developing amenorrhoea appears to be dependent on low energy availability rather than absolute weight because a critical minimum amount of stored, easily mobilized energy is necessary to maintain regular menstrual cycles. Amenorrhoea is often associated with anorexia nervosa and other eating disorders. The female athlete triad is when a woman experiences amenorrhoea, disordered eating, and
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone a ...
. Energy imbalance and weight loss can disrupt menstrual cycles through several hormonal mechanisms. Weight loss can cause elevations in the hormone
ghrelin Ghrelin (; or lenomorelin, INN) is a hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are hi ...
which inhibits the hypothalamic-pituitary-ovarial axis. Elevated concentrations of ghrelin alter the amplitude of
GnRH Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and releas ...
pulses, which causes diminished pituitary release of LH and
follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...
(FSH). Low levels of the hormone
leptin Leptin (from Greek λεπτός ''leptos'', "thin" or "light" or "small") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance by inhibiting hunger, which in turn dimi ...
are also seen in females with low body weight. Like ghrelin, leptin signals energy balance and fat stores to the reproductive axis. Decreased levels of leptin are closely related to low levels of body fat, and correlate with a slowing of GnRH pulsing.


Drug-induced

Certain medications, particularly contraceptive medications, can induce amenorrhoea in a healthy woman. The lack of menstruation usually begins shortly after beginning the medication and can take up to a year to resume after stopping its use. Hormonal contraceptives that contain only progestogen, like the oral contraceptive Micronor, and especially higher-dose formulations, such as the injectable
Depo-Provera Medroxyprogesterone acetate (MPA), also known as depot medroxyprogesterone acetate (DMPA) in injectable form and sold under the brand name Depo-Provera among others, is a hormonal medication of the progestin type. It is used as a method of bir ...
, commonly induce this
side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
. Extended cycle use of combined hormonal contraceptives also allow suppression of menstruation. Patients who stop using
combined oral contraceptive pill The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. The pill contains two important hormones: proges ...
s (COCP) may experience secondary amenorrhoea as a withdrawal symptom. The link is not well understood, as studies have found no difference in hormone levels between women who develop amenorrhoea as a withdrawal symptom following the cessation of COCP use and women who experience secondary amenorrhoea because of other reasons. New contraceptive pills which do not have the normal seven days of placebo pills in each cycle, have been shown to increase rates of amenorrhoea in women. Studies show that women are most likely to experience amenorrhoea after one year of treatment with continuous OCP use. The use of opiates (such as heroin) on a regular basis has also been known to cause amenorrhoea in longer term users. Anti-psychotic drugs, which are commonly used to treat
schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...
, have been known to cause amenorrhoea as well. Research suggests that anti-psychotic medications effect levels of prolactin, insulin, FSH, LH, and testosterone. Recent research suggests that adding a dosage of Metformin to an anti-psychotic drug regimen can restore menstruation. Metformin has been shown to decrease resistance to the hormone
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism ...
, as well as levels of prolactin, testosterone, and luteinizing hormone (LH).


Primary ovarian insufficiency

Primary ovarian insufficiency (POI) affects 1% of females and is defined as the loss of ovarian function before the age of 40. Although the cause of POI can vary, it has been linked to chromosomal abnormalities, chemotherapy, and autoimmune conditions. Hormone levels in POI are similar to menopause and are categorized by low estradiol and high levels of gonadotropins. Since the pathogenesis of POI involves the depletion of ovarian reserve, restoration of menstrual cycles typically does not occur in this form of secondary amenorrhea.


Diagnosis


Primary amenorrhoea

Primary amenorrhoea can be diagnosed in female children by age 14 if no
secondary sex characteristics Secondary sex characteristics are features that appear during puberty in humans, and at sexual maturity in other animals. These characteristics are particularly evident in the sexually dimorphic phenotypic traits that distinguish the sexes of a s ...
, such as enlarged breasts and body hair, are present. In the absence of secondary sex characteristics, the most common cause of amenorrhoea is low levels of FSH and LH caused by a delay in puberty. Gonadal dysgenesis, often associated with
Turner syndrome Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low h ...
, or premature ovarian failure may also be to blame. If secondary sex characteristics are present, but menstruation is not, primary amenorrhoea can be diagnosed by age 16. Evaluation of primary amenorrhea begins with a pregnancy test, prolactin, FSH, LH, and TSH levels. Abnormal TSH levels prompt evaluation for hyper- and hypo-thyroidism with additional thyroid function tests. Elevated prolactin levels prompt evaluation of the pituitary with an MRI to assess for any masses or malignancies. A pelvic ultrasound can also be obtained in the initial evaluation. If a uterus is not present on ultrasound,
karyotype A karyotype is the general appearance of the complete set of metaphase chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is disce ...
analysis and testosterone levels are obtained to assess for MRKH or
androgen insensitivity syndrome Androgen insensitivity syndrome (AIS) is a difference in sex development involving hormonal resistance due to androgen receptor dysfunction. It affects 1 in 20,000 to 64,000 XY ( karyotypically male) births. The condition results in the partial ...
. If a uterus is present, LH and FSH levels are used to make a diagnosis. Low levels of LH and FSH suggest delayed puberty or functional hypothalamic amenorrhea. Elevated levels of FSH and LH suggest primary ovarian insufficiency, typically due to Turner syndrome. Normal levels of FSH and LH can suggest an anatomical outflow obstruction.


Secondary amenorrhea

Secondary amenorrhea's most common and most easily diagnosable causes are
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...
,
thyroid disease Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning ...
, and hyperprolactinemia. A pregnancy test is a common first step for diagnosis. Similar to primary amenorrhea, evaluation of secondary amenorrhea also begins with a pregnancy test, prolactin, FSH, LH, and TSH levels. A pelvic ultrasound is also obtained. Abnormal TSH should prompt a thyroid workup with a full thyroid function test panel. Elevated prolactin should be followed with an MRI to look for masses. If LH and FSH are elevated, menopause or primary ovarian insufficiency should be considered. Normal or low levels of FSH and LH prompts further evaluation with patient history and the physical exam. Testosterone, DHEA-S, and 17-hydroxyprogesterone levels should be obtained if there is evidence of excess androgens, such as hirsutism or acne. 17-hydroxyprogesterone is elevated in congenital adrenal hyperplasia. Elevated testosterone and amenorrhea can suggest PCOS. Elevated androgens can also be present in ovarian or adrenal tumors, so additional imaging may also be needed. History of disordered eating or excessive exercise should raise concern for hypothalamic amenorrhea. Headache, vomiting, and vision changes can be signs of a tumor and needs evaluation with MRI. Finally, a history of gynecologic procedures should lead to evaluation of Asherman syndrome with a hysteroscopy or progesterone withdrawal bleeding test.


Treatment

Treatment for amenorrhea varies based on the underlying condition. Treatment not only focuses on restoring menstruation, if possible, but also preventing additional complications associated with the underlying cause of amenorrhea.


Primary amenorrhea

In primary amenorrhea, the goal is to continue pubertal development, if possible. For example, most patients with Turner syndrome will be infertile due to gonadal dysgenesis. However, patients are frequently prescribed growth hormone therapy and estrogen supplementation to achieve taller stature and prevent osteoporosis. In other cases, such as MRKH, hormones do not need to be prescribed since the ovaries are able to function normally. Patients with constitutional delay of puberty may be monitored by an endocrinologist, but definitive treatment may not be needed as there will eventually be progression to normal puberty.


Secondary amenorrhea

Treatment for secondary amenorrhea varies greatly based on the root cause. Functional hypothalamic amenorrhoea is typically treated by weight gain through increased calorie intake and decreased expenditure. Multidisciplinary treatment with monitoring from a physician,
dietitian A dietitian, medical dietitian, or dietician is an expert in identifying and treating disease-related malnutrition and in conducting medical nutrition therapy, for example designing an enteral tube feeding regimen or mitigating the effects of ...
, and
mental health counselor A mental health counselor (MHC), or counselor (counsellor in British English), is a person who works with individuals and groups to promote optimum mental and emotional health. Such persons may help individuals deal with issues associated with a ...
is recommended, along with support from family, friends, and coaches. Although oral contraceptives can cause menses to return, oral contraceptives should not be the initial treatment as they can mask the underlying problem and allow other effects of the eating disorder, like
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone a ...
, continue to develop. Patients with hyperprolactinemia are often treated with dopamine agonists to reduce the levels of prolactin and restore menstruation. Surgery and radiation may also be considered if dopamine agonists, such as cabergoline and bromocriptine are ineffective. Once prolactin levels are lowered, the resulting secondary amenorrhea is typically resolved. Similarly, treatment of thyroid abnormalities often resolves the associated amenorrhea. For example, administration of thyroxine in patients with low thyroid levels restored normal menstruation in a majority of patients. Although there is currently no definitive treatment for PCOS, various interventions are used to restore more frequent ovulation in patients. Weight loss and exercise have been associated with a return of ovulation in patients with PCOS due to normalization of androgen levels. Metformin has also been recently studied to regularize menstrual cycles in patients with PCOS. Although the exact mechanism still remains unknown, it is hypothesized that this is due to metformin's ability to increase the body's sensitivity to insulin. Anti-androgen medications, such as spironolactone, can also be used to lower body androgen levels and restore menstruation. Oral contraceptive pills are also often prescribed to patients with secondary amenorrhea due to PCOS in order to regularize the menstrual cycle, although this is due to the suppression of ovulation.


References


External links


Disability Online's amenorrhoea page

Disability Online's athletic amenorrhoea page


{{Menstrual cycle Menstrual disorders Reproduction