Amenorrhea

What diagnoses may be considered with a present uterus and high FSH?

A high serum follicle-stimulating hormone (FSH) concentration is indicative of primary ovarian insufficiency (POI; premature ovarian failure). A karyotype is then required and may demonstrate complete or partial deletion of the X chromosome (Turner syndrome) and/or the presence of Y chromatin.

PPP: What is secondary amenorrhea?

Absence of menses for >3 months in a patient with previously normal menstruation (or >6 months in a patient who was previously oligomenorrheic).

PPP: What is the workup for primary amenorrhea?

All women with primary amenorrhea should have hCG and FSH testing most importantly. TSH and prolactin level also usually measured initially. Karyotyping done if increased FSH and little breast development (to rule out Turner's syndrome).

What labs should be measured in the evaluation of primary amenorrhea?

All women with primary amenorrhea should have serum human chorionic gonadotropin (hCG), FSH, thyroid-stimulating hormone (TSH), and prolactin (PRL) measured.

PPP: What is the workup for secondary amenorrhea?

Beta-hCG (to rule out pregnancy) is the best initial test. If hCG negative, order serum prolactin, FSH, LH, TSH and estrogen. Testosterone measured if evidence of hirsutism or hyperandrogenism.

PPP: What is primary amenorrhea?

Failure of menarche onset by age 15 years (in the presence of secondary sex characteristics) or age 13 years (in the absence of secondary sex characteristics).

What diagnoses may be considered with an absent uterus?

For those with absence of the uterus, further evaluation should include a karyotype and measurement of serum total testosterone.

What are hypothalamic and pituitary causes of primary amenorrhea?

Hypothalamic causes of primary amenorrhea are functional hypothalamic amenorrhea and isolated GnRH deficiency. Less commonly, tumors and infiltrative lesions of the hypothalamus or pituitary can result in amenorrhea, usually in association with hyperprolactinemia.

What is secondary amenorrhea?

Missing a single menstrual period may not be important to assess, but amenorrhea lasting three months or more and oligomenorrhea (fewer than nine menstrual cycles per year or cycle length greater than 35 days) require investigation. An intermenstrual interval greater than 45 days is considered abnormal in adolescent girls who are ≥2 years postmenarche.

How should you approach the evaluation of secondary amenorrhea?

Once pregnancy has been ruled out, a logical approach to women with either primary or secondary amenorrhea is to consider disorders based upon the levels of control of the menstrual cycle: hypothalamus, pituitary, ovary, and uterus. Determining the site of the defect is important because it determines the appropriate therapeutic regimen. While the most common causes of secondary amenorrhea are likely to be functional hypothalamic amenorrhea or polycystic ovary syndrome (PCOS), disorders with an anatomic or pathologic cause must be ruled out.

How does polycystic ovarian syndrome (PCOS) cause secondary amenorrhea?

PCOS, the most common reproductive disorder in women, accounts for approximately 20 percent of cases of amenorrhea but may account for approximately 50 percent of cases of oligomenorrhea. The principal features of PCOS include androgen excess, ovulatory dysfunction, and/or polycystic ovaries. In addition, many women with PCOS are overweight or obese and have insulin resistance. Women with PCOS may present with amenorrhea, but they more commonly have irregular menses (oligomenorrhea). The minimal criteria for the diagnosis of PCOS are two out of three of the following: (1) hyperandrogenism, (2) oligomenorrhea or amenorrhea, and (3) polycystic ovaries on ultrasound.

What is primary amenorrhea?

Primary amenorrhea is defined as the absence of menses at age 15 years in the presence of normal growth and secondary sexual characteristics. The identification of primary amenorrhea should always prompt a thorough evaluation to identify a cause.

PPP: What are pituitary causes of secondary amenorrhea?

Prolactinoma or pituitary infarct (Sheehan syndrome). Associated with decreased FSH, LH and estrogen.

PPP: Uterus absent, breast absent

Rare. Usually caused by a defect in testosterone synthesis. Presents like a phenotypic immature girl with primary amenorrhea (will often have intra-abdominal testes).

What are systemic illnesses in primary amenorrhea?

Systemic illness can cause secondary or primary amenorrhea when it is severe enough to result in a decrease in hypothalamic GnRH secretion. Examples include celiac disease, type 1 diabetes mellitus, and inflammatory bowel disease

How does systemic illness cause secondary amenorrhea?

Systemic illness may be associated with menstrual cycle disorders when it is severe enough to result in a decrease in hypothalamic GnRH secretion and/or when it is associated with nutritional deficiencies. Examples include type 1 diabetes mellitus and celiac disease, which may also present with autoimmune ovarian insufficiency.

How does primary ovarian insufficiency (POI) cause secondary amenorrhea?

The depletion of oocytes before age 40 years is called primary ovarian insufficiency (POI, or premature ovarian failure). Most women experience intermittent follicular development, estradiol production, LH surges, ovulation, and menstrual bleeding between months of hypoestrogenemia. When POI is complete, lack of ovarian function leads to estrogen deficiency, endometrial atrophy, and cessation of menstruation. POI may be due to complete or partial loss of an X chromosome (Turner syndrome), the fragile X premutation, autoimmune ovarian destruction, or, most commonly, unknown and rare causes.

What is 46, XY dysgenesis?

The estimated prevalence of 46,XY gonadal dysgenesis is 1:100,000 births. In complete 46,XY gonadal dysgenesis, the fibrous streak gonad cannot secrete anti-müllerian hormone (AMH). This results in persistent müllerian structures and a female phenotype. The phenotype of partial gonadal dysgenesis can range from genital ambiguity to an undervirilized male. Mutations in SRY, FOG2/ZFPM2, and WNT1 have been identified. Because of the phenotypic variability, some patients are diagnosed in infancy with ambiguous genitalia, while others are not diagnosed until puberty when they present with primary amenorrhea.

What should be included in the physical examination for secondary amenorrhea?

The examination in women with secondary amenorrhea should include measurements of height and weight. The patient should also be examined for hirsutism, acne, striae, acanthosis nigricans, vitiligo, and easy bruisability. Breasts should be examined for evidence of galactorrhea, and a vulvovaginal exam should look for signs of estrogen deficiency.

What laboratory testing should be obtained for secondary amenorrhea?

The initial laboratory evaluation (after ruling out pregnancy) for women with secondary amenorrhea should include follicle-stimulating hormone (FSH), serum PRL, and thyroid-stimulating hormone (TSH). If there is clinical evidence of hyperandrogenism (hirsutism, acne, scalp hair loss [alopecia]), serum total testosterone should be measured in addition to the initial laboratory tests.

How is hyperprolactinemia treated?

The management of women with amenorrhea due to hyperprolactinemia depends upon the cause of the hyperprolactinemia and the patient's goals (eg, pursuing fertility or not).

What are treatment goals for secondary amenorrhea?

The overall goals of management in women with secondary amenorrhea include: 1) Correcting the underlying pathology, if possible 2) Helping the woman to achieve fertility, if desired 3) Preventing complications of the disease process (eg, estrogen replacement to prevent osteoporosis)

What is the treatment for isolated GnRH deficiency?

The same considerations apply to women with hypothalamic or pituitary dysfunction that is not reversible (eg, congenital GnRH deficiency). For women who want to become pregnant, either exogenous gonadotropins or pulsatile GnRH can be given.

What are important components of the physical examination for evaluation of primary amenorrhea?

The single most important step in the evaluation is to determine by physical examination (or ultrasonography if needed) if a uterus is present. In addition, the vagina and cervix should be examined for anatomic abnormalities. Other findings on physical examination that can provide clues to the etiology of the amenorrhea include: -Breast development -Growth (height, weight, arm span) -Skin findings (hirsutism, acne, striae, increased pigmentation, and vitiligo) -Physical features of Turner syndrome (low hairline, webbed neck, shield chest, and widely spaced nipples) A careful genital examination should be performed for clitoral size, pubic hair development, intactness of the hymen, vaginal length, and presence of a cervix, uterus, and ovaries.

How are intrauterine adhesions treated?

Therapy of Asherman syndrome (intrauterine adhesions) consists of hysteroscopic lysis of adhesions followed by a course of estrogen treatment to stimulate regrowth of endometrial tissue.

How is polycystic ovarian syndrome (PCOS) treated?

Treatment of hyperandrogenism is directed toward achieving the woman's goal (eg, relief of hirsutism, resumption of menses, fertility) and preventing the long-term consequences of polycystic ovary syndrome (PCOS), such as endometrial hyperplasia, obesity, and metabolic disorders.

What is Turner syndrome?

Women with Turner syndrome are missing all of one X chromosome in 55 to 60 percent of cases (45,X gonadal dysgenesis). Amenorrhea occurs because the oocytes and follicles undergo accelerated apoptosis (in utero in most cases). The ovaries are replaced with fibrous tissue, and in the absence of follicles, there is no ovarian estrogen secretion. In contrast, the external female genitalia, uterus, and fallopian tubes develop normally until puberty when estrogen-induced maturation fails to occur. Spontaneous puberty and menstruation occur more commonly in women with a mosaic karyotype (45,X/46,XX) but can occur in women with a 45,X karyotype, although spontaneous pregnancy is unlikely with a 45,X karyotype. Women with Turner syndrome whose karyotype includes a Y chromosome (such as 45,X/46,XY mosaicism) are at increased risk for gonadoblastoma, a neoplasm that occurs in dysgenetic gonads.

What are important historical questions to ask in the evaluation of primary amenorrhea?

1) Has she completed other stages of puberty, including a growth spurt, development of axillary and pubic hair, apocrine sweat glands, and breast development? 2) Is there a family history of delayed or absent puberty (suggesting a possible familial disorder)? 3) What is the woman's height relative to family members? 4) Were neonatal and childhood health normal? 5) Are there any symptoms of hyperandrogenism (acne, hirsutism) or virilization? 6) Has there been stress; change in weight, diet, or exercise habits; or illness? 7) Is she taking any drugs that might cause or be associated with amenorrhea? 8) Does she have galactorrhea, which would suggest excess prolactin? 9) Are there symptoms of other hypothalamic-pituitary disease, including headaches, visual field defects, fatigue, or polyuria and polydipsia?

What is primary ovarian insufficiency (POI)?

46,XX primary ovarian insufficiency (POI) is defined as the development of clinical menopause before the age of 40 years in women who have a normal karyotype. POI usually presents as secondary amenorrhea and can be due to chemotherapy or radiation, autoimmune oophoritis, an FMR1 premutation, or a number of mutations. Although most women present with secondary amenorrhea, some present with primary amenorrhea.

What is 5-alpha-reductase deficiency?

5-alpha-reductase deficiency is another congenital defect that can result in primary amenorrhea in a 46,XY subject. At birth, these neonates may appear female or have ambiguous genitalia due to an inability to convert testosterone (via 5-alpha-reductase) to its more potent metabolite dihydrotestosterone (DHT). At puberty, the disorder is more recognizable because of the onset of virilization (male-pattern hair growth, increased muscle mass, and voice deepening) due to the normal peripubertal increase in testosterone secretion in males. However, these individuals do not undergo DHT-dependent masculinization (enlargement of the male external genitalia and prostate).

What is estrogen resistance?

A mutation in the gene encoding estrogen receptor-alpha (ESR1), which had previously been described only in a male, has now been identified in an 18-year-old girl with primary amenorrhea and profound estrogen resistance. She presented with very high serum estradiol concentrations (3500 pg/mL [12,849 pmol/L]), inappropriately elevated serum gonadotropins (LH 9.6 mIU/mL, FSH 6.7 mIU/mL), enlarged multicystic ovaries, and no evidence of endometrial thickening. In spite of the hyperestrogenemia, she had normal serum concentrations of sex hormone-binding globulin (SHBG), cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG), and triglycerides. She also had delayed bone age (13.5 years), low bone mineral density (BMD) (Z-score -2.4), and her growth velocity chart suggested a lack of an estrogen-induced adolescent growth spurt. DNA sequencing identified a homozygous mutation in ESR1 that severely impaired estrogen signaling except with administration of pharmacologic doses of estrogen, when minimal signaling was observed. The prevalence of ESR1 mutations in humans is unknown, but they are likely to be very rare. Although they have not been identified clinically, milder ESR1 mutations could result in incomplete estrogen resistance analogous to the partial androgen insensitivity syndrome caused by mild mutations in the androgen receptor gene.

What should be the first step when evaluating any woman with secondary amenorrhea?

A pregnancy test is recommended as a first step in evaluating any woman with secondary amenorrhea. Measurement of serum beta subunit of human chorionic gonadotropin (hCG) is the most sensitive test.

What is isolated GnRH deficiency?

Although rare, primary amenorrhea can be due to complete congenital gonadotropin-releasing hormone (GnRH) deficiency. This syndrome is called idiopathic hypogonadotropic hypogonadism or, if it is associated with anosmia, Kallmann syndrome. These women typically have apulsatile and prepubertal low serum gonadotropin concentrations due to the absence of hypothalamic GnRH. This disorder is often difficult to distinguish clinically from constitutional delay of puberty. Isolated GnRH deficiency can be inherited as an autosomal dominant, autosomal recessive, or X-linked condition.

What is amenorrhea?

Amenorrhea (absence of menses) can be a transient, intermittent, or permanent condition resulting from dysfunction of the hypothalamus, pituitary, ovaries, uterus, or vagina.

How does pituitary disease cause secondary amenorrhea?

Among pituitary disorders that cause secondary amenorrhea, lactotroph adenomas (prolactin-secreting pituitary adenomas, prolactinomas) are the most common. They are responsible for 13 percent of cases of secondary amenorrhea and 90 percent of the cases due to pituitary disease.

What is an imperforate hymen?

An imperforate hymen is the simplest defect that results in primary amenorrhea. It may be associated with cyclic pelvic pain and a perirectal mass from sequestration of blood in the vagina (hematocolpos). Similar findings can be seen with defects in perineal development, which can result in absence of the distal third of the vagina and therefore absence of an outflow tract. Both of these conditions are diagnosed by physical examination. An imperforate hymen is easily corrected with surgery.

PPP: What are uterine causes of secondary amenorrhea?

Asherman's syndrome: acquired endometrial scarring secondary to post-partum hemorrhage, after D&C or endometrial infection. Pelvic ultrasound- absence of the normal uterine stripe. Hysteroscopy.

When should investigation for primary amenorrhea begin?

At age 13 years, if no menses have occurred and there is a complete absence of secondary sexual characteristics such as breast development, evaluation for primary amenorrhea should begin. In addition, some girls with secondary sexual characteristics may present before age 15 years with amenorrhea and cyclic pelvic pain. These girls should be evaluated for possible outflow tract obstruction.

What are outflow tract disorders?

Congenital abnormalities of the female reproductive organs account for approximately 20 percent of cases of primary amenorrhea. Menses cannot occur without an intact uterus, endometrium, cervix, cervical os, and vaginal conduit. Pelvic or lower abdominal pain is a common presenting symptom in girls with primary amenorrhea and an obstructed reproductive tract.

What is constitutional delay of puberty?

Constitutional delay of puberty is common in boys with a family history of delayed puberty, but it is fivefold less common in girls. Constitutional delay is characterized by both delayed adrenarche and gonadarche, and it is often difficult to distinguish clinically from congenital GnRH deficiency. Patients with constitutional delay go on to have completely normal pubertal development, albeit at a later age. Because constitutional delay of puberty is uncommon in girls, it should be a diagnosis of exclusion.

PPP: What are ovarian causes of secondary amenorrhea?

Decreased estrogen and increased FSH and LH. Polycystic ovarian syndrome. Premature ovarian failure: follicular failure or follicular resistance to LH or FSH. Turner syndrome. May have symptoms of estrogen deficiency (similar to menopause).

PPP: Uterus present, breast absent

Elevated: FSH, LH--> ovarian causes -Premature ovarian failure (46XX) -Gonadal dysgenesis (Turner's 45X) Normal/low: FSH, LH -Hypothalamus-pituitary failure -Puberty delay (e.g. athletes, illness, anorexia)

What is the treatment for functional hypothalamic amenorrhea?

Functional hypothalamic amenorrhea can usually be reversed by weight gain, reduction in the intensity of exercise, and/or resolution of illness or emotional stress.

What is functional hypothalamic amenorrhea?

Functional hypothalamic amenorrhea is a disorder that, by definition, excludes pathologic disease. It is characterized by abnormal hypothalamic GnRH secretion leading to decreased gonadotropin pulsations, low or normal serum luteinizing hormone (LH) concentrations, absent LH surges, absence of normal follicular development, anovulation, and low serum concentrations of estradiol. Serum follicle-stimulating hormone (FSH) concentrations are often in the normal range, with a high FSH-to-LH ratio similar to the pattern in prepubertal girls. Multiple factors may contribute to the pathogenesis of functional hypothalamic amenorrhea, including eating disorders (such as anorexia nervosa), exercise, and stress. The term hypothalamic amenorrhea is often used interchangeably with functional hypothalamic amenorrhea.

How does functional hypothalamic amenorrhea cause secondary amenorrhea?

Functional hypothalamic amenorrhea, or functional hypothalamic GnRH deficiency, is a disorder that, by definition, excludes pathologic disease. It is characterized by a presumed decrease in hypothalamic GnRH secretion. The abnormal GnRH secretion characteristic of functional hypothalamic amenorrhea leads to decreased pulses of gonadotropins, absent midcycle surges in luteinizing hormone (LH) secretion, absence of normal follicular development, anovulation, and low serum estradiol concentrations. One of the main clinical concerns in women with functional hypothalamic amenorrhea is bone loss due to hypoestrogenemia.

PPP: What are hypothalamic causes of secondary amenorrhea?

Functional hypothalamic amenorrhea. Puberty delay due (e.g. athletes, illness, anorexia). The female athlete triad: hypothalamic amenorrhea, eating disorder and osteoporosis (due to loss of bone protection by estrogen). FHA can cause primary or secondary amenorrhea.

What diagnoses may be considered with a present uterus, low/normal FSH and no evidence of breast development?

Girls with low or normal FSH and no evidence of breast development most likely have a central hypothalamic-pituitary disorder; they should have a second serum sample obtained for both luteinizing hormone (LH) and FSH measurements.

What diagnoses may be considered with a present uterus and a low or normal FSH?

Girls with low/normal FSH and breast development have either an anatomic abnormality (which is identified on ultrasound) or an endocrine disorder such as PCOS, hyperprolactinemia, or thyroid disease, disorders that more commonly cause secondary amenorrhea.

What are the most common medical conditions associated with primary amenorrhea?

Gonadal dysgenesis, including Turner syndrome - 43% Müllerian agenesis (absence of vagina, sometimes with absence of uterus) - 15% Physiologic delay of puberty (constitutional delay of puberty, chronic systemic disease, acute illness) - 14% -Of note, constitutional delay of puberty is common in boys but uncommon in girls Polycystic ovary syndrome (PCOS) - 7% Isolated gonadotropin-releasing hormone (GnRH) deficiency - 5% Transverse vaginal septum - 3% Weight loss/anorexia nervosa - 2% Hypopituitarism - 2% Less common etiologies (≤1 percent each) included imperforate hymen, complete androgen insensitivity syndrome, hyperprolactinemia/prolactinoma, other pituitary tumors, congenital adrenal hyperplasia, hypothyroidism, central nervous system defects, craniopharyngioma, and Cushing's disease.

What are important historical questions for secondary amenorrhea?

Has there been stress, change in weight, diet, or exercise habits, or is there an eating disorder or illness? Is the woman taking any drugs that might cause or be associated with amenorrhea? Is there hirsutism, acne, and a history of irregular menses? Are there symptoms of hypothalamic-pituitary disease, including headaches, visual field defects, fatigue, or polyuria and polydipsia? Are there any symptoms of estrogen deficiency, including hot flashes, vaginal dryness, poor sleep, or decreased libido? Has the patient had galactorrhea? Is there a history of obstetrical catastrophe, severe bleeding, dilatation and curettage, or endometritis or other infection that might have caused scarring of the endometrial lining?

How does hyperprolactinemia cause secondary amenorrhea?

Hyperprolactinemia has a similar presentation to functional hypothalamic amenorrhea, except for the additional finding of galactorrhea in some women. As a result, serum prolactin should be measured in every woman with amenorrhea. The normal range should be consulted for the prolactin assay used, as the upper limit of normal for women of reproductive age can range from 20 to 27 ng/mL (20 to 27 mcg/L). Prolactin appears to cause amenorrhea by suppressing hypothalamic GnRH secretion, leading to low gonadotropin and estradiol concentrations. Unlike the other pituitary hormones, prolactin release is mostly controlled by inhibition, primarily by hypothalamic dopamine.

What is hyperprolactinemia?

Hyperprolactinemia is a common cause of secondary amenorrhea but an uncommon cause of primary amenorrhea. The presentation is similar to hypothalamic amenorrhea except for the additional finding of galactorrhea in some patients. A serum prolactin concentration above the normal range for nonpregnant women of reproductive age (often 15 to 20 ng/mL or 15 to 20 mcg/L) is considered abnormal. Stress, sleep, exercise, intercourse, and meals can raise serum prolactin concentrations transiently. Thus, we recommend that high serum prolactin concentrations be recorded at least twice before magnetic resonance imaging (MRI) is ordered.

How do hypothalamic tumors and infiltrative lesions cause secondary amenorrhea?

Hypothalamic tumors, (eg, craniopharyngiomas, lymphomas) and infiltrative diseases (eg, Langerhans cell histiocytosis, sarcoidosis) may result in decreased GnRH secretion, low or normal serum gonadotropin concentrations, and amenorrhea. However, these lesions are uncommon compared with functional hypothalamic amenorrhea. Most women with infiltrative disease of the hypothalamus who have amenorrhea will have one or more neurologic symptoms, such as severe headache, change in personality, or marked mood changes.

What is the treatment for PCOS?

In women with polycystic ovary syndrome (PCOS), treatment of hyperandrogenism is directed toward achieving the woman's goal (eg, relief of hirsutism, resumption of menses, fertility) and preventing the long-term consequences of PCOS (eg, endometrial hyperplasia/cancer, obesity, and metabolic defects).

How do uterine disorders cause secondary amenorrhea?

Intrauterine adhesions (Asherman syndrome) are the only uterine cause of secondary amenorrhea. This syndrome results from acquired scarring of the endometrial lining, usually secondary to postpartum hemorrhage or endometrial infection followed by instrumentation such as a dilatation and curettage. This abnormality prevents the normal build-up and shedding of endometrial cells, leading to very light or absent menses.

What are the types of amenorrhea?

It is often classified as either primary (absence of menarche by age 15 years) or secondary (absence of menses for more than three cycle intervals or six months in women who were previously menstruating).

How is hypothalamic amenorrhea treated?

Lifestyle changes, cognitive behavioral therapy, and management of low bone density with estrogen therapy.

What are infiltrative diseases and tumors in primary amenorrhea?

Many infiltrative diseases and tumors of the hypothalamus and pituitary can result in diminished GnRH release or gonadotrope destruction and amenorrhea; these include craniopharyngioma, germinoma, and Langerhans cell histiocytosis. The main indications for MRI are hypogonadotropic hypogonadism, visual field defects, headaches, other evidence of hypothalamic or pituitary dysfunction, or symptoms suggestive of other diseases

How does thyroid disease cause secondary amenorrhea?

Menstrual cycle disorders are common in women with thyroid disease. Although heavy bleeding is the typical bleeding pattern seen with hypothyroidism, secondary amenorrhea can also occur.

What is polycystic ovarian syndrome (PCOS)?

Most cases of PCOS present with oligomenorrhea, but occasionally secondary amenorrhea and rarely primary amenorrhea, may be present. The menstrual disturbances in women with PCOS classically have a peripubertal onset. The women with PCOS who present with primary amenorrhea typically have higher androgen levels and are more overweight. However, most have a slightly early menarche related to overweight, followed by irregular cycles (oligomenorrhea) or secondary amenorrhea. The diagnosis can be made in a girl with clinical and biochemical evidence of hyperandrogenism in the presence of advanced pubertal development (ie, greater than or equal to Tanner stage 4 breast development) and in the absence of other disorders causing amenorrhea and hyperandrogenism.

PPP: Uterus absent, breast present

Mullerian agenesis (46 XX) Androgen insensitivity (46 XY)

What are risk factors for functional hypothalamic amenorrhea?

Multiple factors may contribute to the pathogenesis of functional hypothalamic amenorrhea, including eating disorders (such as anorexia nervosa), excessive exercise, and stress. However, in a few women with functional hypothalamic amenorrhea, no obvious precipitating factor is evident. The term hypothalamic amenorrhea is often used interchangeably with functional hypothalamic amenorrhea. The "female athlete triad" is defined as the presence of amenorrhea, disordered eating, and osteoporosis or osteopenia.

What is Mullerian agenesis?

Müllerian agenesis, also known as vaginal agenesis or Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, refers to congenital absence of the vagina with variable uterine development. It is usually accompanied by cervical and uterine agenesis; however, 7 to 10 percent of women have a normal but obstructed or rudimentary uterus with functional endometrium. The defect results from agenesis or hypoplasia of the müllerian duct system. Heterozygous mutations in WNT4 account for a small subset of these cases. The most commonly cited incidence for vaginal agenesis is 1 in 5000 (range: 1 per 4000 to 10,000 females).

What is a transverse vaginal septum?

One or more transverse vaginal septae can occur at any level between the hymenal ring and the cervix. After menarche, the major symptoms are similar to those associated with an imperforate hymen.

PPP: Uterus present, breast present

Outflow obstruction: transverse vaginal septum, imperforate hymen.

What are causes of secondary amenorrhea?

Pregnancy is #1 Ovary - 40% (30 percent polycystic ovary syndrome [PCOS], 10 percent primary ovarian insufficiency [POI, also known as premature ovarian failure]) Hypothalamus - 35% (almost all functional hypothalamic amenorrhea) Pituitary - 17% (13 percent hyperprolactinemia, 1.5 percent "empty sella," 1.5 percent Sheehan syndrome, 1 percent Cushing's syndrome) Uterus - 7% (all due to intrauterine adhesions) Other - 1% (congenital adrenal hyperplasia, ovarian and adrenal tumors, hypothyroidism)

What is the most common cause of secondary amenorrhea?

Pregnancy is the most common cause of secondary amenorrhea. Thus, a pregnancy test (measurement of serum or urinary human chorionic gonadotropin [hCG]) is recommended as a first step in evaluating any woman with amenorrhea.

PPP: What are the etiologies of secondary amenorrhea?

Pregnancy is the most common cause. Hypothalamus dysfunction Pituitary dysfunction Ovarian dysfunction Uterine dysfunction

How should you approach evaluation of primary amenorrhea?

Primary amenorrhea is evaluated most efficiently by focusing on the presence or absence of breast development (a marker of estrogen action and therefore function of the ovary), the presence or absence of the uterus (as determined by ultrasound, or in more complex cases by magnetic resonance imaging [MRI]), and the follicle-stimulating hormone (FSH) level.

What is the etiology of primary amenorrhea?

Primary amenorrhea is usually the result of a genetic or anatomical abnormality. However, all causes of secondary amenorrhea can also present as primary amenorrhea.

What is the treatment for patients with congenital anatomic lesions or Y chromosome material?

Surgery may be required in patients with either congenital anatomic lesions or Y chromosome material. The etiology of the primary amenorrhea will determine the type of surgical procedure required. As an example, surgical correction of a vaginal outlet obstruction is necessary as soon as the diagnosis is made after menarche to allow passage of menstrual blood. Creation of a neovagina for patients with müllerian failure is usually delayed until the women are emotionally mature and ready to participate in the postoperative care required to maintain vaginal patency. In those patients in whom Y chromosomal material is found, gonadectomy should be performed to prevent the development of gonadal neoplasia.

What is P450 oxidoreductase (POR) deficiency?

The P450 oxidoreductase (POR) donates electrons to cytochrome P450 enzymes, including 17-alpha-hydroxylase/17,20-lyase. Oxidoreductase deficiency has two unique clinical features. First, affected neonates may present with severe undervirilization in boys and severe virilization in girls. In addition, patients may present with a complex, predominantly craniofacial pattern, termed Antley-Bixler syndrome. The spectrum of POR mutations has expanded and includes women with primary amenorrhea and infertility. Women might present with a pattern of atypical congenital adrenal hyperplasia upon ACTH stimulation, including low cortisol and androstenedione levels and elevated 17-hydroxyprogesterone and progesterone levels. Women may also present with amenorrhea in the setting of multiple large ovarian cysts but low estradiol levels.

What is complete androgen insensitivity syndrome?

The complete androgen insensitivity syndrome is an X-linked recessive disorder in which 46,XY subjects have a normal female phenotype. These patients are resistant to testosterone due to a defect in the androgen receptor and, therefore, fail to develop all of the male sexual characteristics that are dependent upon testosterone. The external genitalia are typically female in appearance, but testes may be palpable in the labia or inguinal area. The testes make müllerian-inhibiting substance, which is functional and causes regression of all müllerian structures: the fallopian tubes, uterus, and upper third of the vagina. At puberty, breast development occurs, but the areolae are pale and pubic and axillary hair is sparse. Carrier females (46,XX) develop normal internal and external genitalia. The diagnosis of this disorder is based upon the absence of the upper vagina, uterus, and fallopian tubes on physical examination and pelvic ultrasonography; high serum testosterone concentrations (in the range for normal men); and a male (46,XY) karyotype. The testes should be surgically excised after puberty because of the increased risk (2 to 5 percent) of developing testicular cancer after age 25 years.

What is gonadal dysgenesis/primary ovarian insufficiency?

The most common cause of primary amenorrhea is gonadal dysgenesis caused by chromosomal or genetic abnormalities. These disorders result in premature depletion of all ovarian oocytes and follicles. These women have significantly elevated FSH levels due to the absence of ovarian oocytes and follicles, leading to reduced negative feedback on FSH from estradiol and inhibin B. The largest number of patients have Turner syndrome (45,X as well as other karyotypes), followed by 46,XX gonadal dysgenesis (typically autosomal) and, rarely, 46,XY gonadal dysgenesis.

What is 17-alpha-hydroxylase deficiency?

This rare disorder, which can occur in 46,XX or 46,XY subjects, is characterized by deficiency of the product of the CYP17 gene, which is an enzyme that has both 17-hydroxylase and 17,20-lyase activities. As a result, there is decreased cortisol synthesis but overproduction of corticotropin (ACTH), corticosterone, and deoxycorticosterone. Adrenal and gonadal sex steroids are not produced, so that affected subjects typically present as phenotypic females with hypertension (due to mineralocorticoid excess), lack of pubertal development, and either female (if 46,XX) or incompletely developed (if 46,XY) external genitalia.

What are treatment goals of primary amenorrhea?

Treatment of primary amenorrhea is directed at correcting the underlying pathology (if possible), helping the woman to achieve fertility (if desired), and prevention of complications of the disease process (eg, estrogen replacement to prevent osteoporosis).

What is the treatment for primary ovarian insufficiency (POI)?

Women with primary ovarian insufficiency (POI) should be counseled regarding the benefits and risks of hormone therapy. In general, in women of reproductive age with hypoestrogenism, hormone replacement is important to prevent bone loss and to prevent the potential excess risk of premature coronary heart disease.

How is primary ovarian insufficiency (POI) treated?

Women with primary ovarian insufficiency (POI) should receive estrogen therapy for prevention of bone loss. This can be either an oral contraceptive (if the patient is having intermittent ovarian function and does not wish to become pregnant) or replacement doses of estrogen and progestin.