Amenorrhea

Although amenorrhea has multiple potential causes, ultimately, it is the result of a hormonal imbalance or an anatomical abnormality. Physiologically, menstruation is controlled by the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus. 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 amenorrhea 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. It produces the appearance of secondary sexual characteristics, which are the sprouting of pubic and armpit hair, development of the breasts, and a lack of definition in the female body structure, such as the waist and hips. Secondary amenorrhea Secondary amenorrhea 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, 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. Most people with Turner syndrome experience ovarian insufficiency within the first few years of life, before menarche. The syndrome is characterized by Müllerian agenesis. In MRKH Syndrome, the Müllerian ducts develop abnormally and result in the absence of a uterus and cervix. 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. This may be due to genetics, as some cases of constitutional delay of puberty are familial. 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 amenorrhea, and the duration of amenorrhea 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. Patients with hypothyroidism frequently present with changes in their menstrual cycle. Prolactin secreting pituitary adenomas cause amenorrhea due to the hyper-secretion of prolactin which inhibits FSH and LH release. Polycystic ovary syndrome Polycystic ovary syndrome (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. PCOS may also be a cause of primary amenorrhea if androgen access is present prior to menarche. Functional hypothalamic amenorrhea (FHA) can be caused by stress, weight loss, or excessive exercise. Amenorrhea is often associated with anorexia nervosa and other eating disorders. Relative energy deficiency in sport, also known as the female athlete triad, is when a woman experiences amenorrhea, disordered eating, and osteoporosis. Weight loss can cause elevations in the hormone ghrelin which inhibits the hypothalamic-pituitary-ovarial axis. Low levels of the hormone leptin are also seen in females with low body weight. Like ghrelin, leptin signals energy balance and fat stores to the reproductive axis. The lack of menstruation usually begins shortly after beginning the medication and can take up to a year to resume after stopping its use. Extended cycle use of combined hormonal contraceptives also allow suppression of menstruation. Patients who stop using combined oral contraceptive pills (COCP) may experience secondary amenorrhea as a withdrawal symptom. Anti-psychotic drugs, which are commonly used to treat schizophrenia, have been known to cause amenorrhea as well. Research suggests that anti-psychotic medications affect levels of prolactin, insulin, FSH, LH, and testosterone. 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 amenorrhea Primary amenorrhea can be diagnosed in female children by age 14 if no secondary sex characteristics, such as enlarged breasts and body hair, are present. If a uterus is present, LH and FSH levels are used to make a diagnosis. Secondary amenorrhea Secondary amenorrhea's most common and most easily diagnosable causes are pregnancy, thyroid disease, and hyperprolactinemia. A pregnancy test is a common first step for diagnosis. 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. However, patients are frequently prescribed growth hormone therapy and estrogen supplementation to achieve taller stature and prevent osteoporosis. 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 amenorrhea is typically treated by weight gain through increased calorie intake and decreased expenditure. Multidisciplinary treatment with monitoring from a physician, dietitian, and mental health counselor is recommended, along with support from family, friends, and coaches. 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 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 to regularize the menstrual cycle, although this is due to the suppression of ovulation. == References ==