3- Primary Amenorrhea

Hypogonadotropic hypogonadism

Examples of this disorder are CNS or pituitary tumor, constitutionally delayed puberty, and Kallmann syndrome (characterized by anosmia) which rarely presents as secondary amenorrhea with late onset These usually result in primary amenorrhea with sexual infantilism

estrogen + progestin (E-P) test

If a patient has a negative progestin withdrawal bleed test when determining if amenorrhea is disorder of outflow tract or uterus, retest the patient with this test Patients are given conjugated estrogen 2.5mg daily for 21 days and provera 10mg daily for 17-21 days. If negative (no bleed), differential diagnosis includes Mullerian abnormalities, Asherman's syndrome (intrauterine adhesion), testicular feminization, and tuberculosis/schistosomiasis If positive (withdrawal bleed), differential diagnosis includes ovarian disorder, CNS disorder (hypothalamic), or anterior pituitary disorder

androgen insensitivity syndrome (AIS)

In this syndrome, there is a defect in the androgen receptor in 46XY males, resulting in primary amenorrhea with breast development and Mullerian anomalies. Patients have male levels of testosterone, and mildly elevated FSH and LH (due to ovaries within abdominal wall). Testicular secretion of estrogen, and conversion of circulating androgen to estrogen result in breast development The (misplaced) testis secrete normal amount of anti-mullerian hormone, thus NO uterus is present, only vaginal dimple

Turner's syndrome

In this syndrome, there is an abnormality or absence of one of the X chromosomes (45XO) in all cell lines. Patients have streak gonads with an absence of ovarian follicles, which can present as primary amenorrhea/sexual infantilism These patients typically present with primary amenorrhea, short stature, webbed neck (pterygium colli), shield chest with widely spaced nipples, high-arched palate, and an increased carrying angle of the elbow (cubitus valgus)

androgens

Normal amounts of pubic and axillary hair seen with amenorrhea confirms gonadal or adrenal secretion of these hormones and the presence of their receptors

Hypothalamic anovulation

Patients with amenorrhea (or oligomenorrhea) with normal estrogen levels may have a mild form of this This can be due to low body weight, exercise issues, psychological stress, recent pregnancy, lactation, or medications (re. depo provera) If so, patients are given periodic progestin to protect endometrium. If they have adequate estrogen, these patients will have withdrawal bleed

hyperandrogenism

This can cause secondary amenorrhea (or oligomenorrhea) with breast development and normal mullerian structures. This shows elevated androgens (variable) Examples are congenital adrenal hyperplasia (CAH), polycystic ovarian syndrome (PCOS), and HAIR-AN syndrome Clinical features include hirsutism, acne, insulin resistance, and virilization in some severe cases

Mullerian dysgenesis/agenesis

This can occur in individuals with 46XX karyotype with serum testosterone levels that are normal for female, but has primary amenorrhea with breast development and Mullerian anomalies These mullerian defects include imperforate hymen, transverse vaginal septum, absence of cervix, uterus, tubes and upper vagina. There are frequently associated renal abnormalities so you want to image to confirm normal urinary system During fetal life, the mullerian ducts develop and fuse in the female fetus to form the upper reproductive tract: uterus, fallopian tubes and upper vagina. The lower and midportion of the vagina develop from the canalization of the genital plate

hypergonadotropic hypogonadism

This cause of primary amenorrhea with sexual infantilism results from failed gonadal development or premature gonadal failure. This is characterized by ELEVATED FSH and low estrogen All patients with this should have a karyotype. Patients with sexual infantilism may be treated to stimulate breast development with Estrogen at puberty, and Growth Hormone (GH) early to normalize height

breast development

This development seen in amenorrhea confirms estrogen secretion, but may not be ovarian origin Example includes androgen insensitivity, in which low levels of estrogen from testicles may stimulate this development in genotypic males

premature ovarian failure

This differential diagnosis for hypoestrogenism in patients with amenorrhea with normal breast development and mullerian structures is characterized by high FSH and normal PRL. In this, ovarian follicles are either exhausted or resistant to FSH/LH This occurs in females ages < 40. If < 30, do a karyotype. This has chromosomal causes (Turner syndrome, X-chromosome long arm deletion), and other causes such as Savage syndrome, premature natural menopause and autoimmune ovarian failure This is treated with E/P therapy to prevent osteoporosis

hypothalamic-pituitary dysfunction

This differential diagnosis for hypoestrogenism in patients with amenorrhea with normal breast development and mullerian structures is characterized by low FSH and low PRL Check out other pituitary hormones and obtain an MRI of the hypothalamus for diagnosis. This can be have functional causes (weight loss, excessive exercise), drug-induced, neoplastic causes, psychogenic causes, and others This is treated with estrogen-progesterone therapy (low dose OC), to prevent osteoporosis

Asherman's syndrome

This disorder of Outflow Tract is the most common anatomic cause of secondary amenorrhea that can be caused by multiple dilation and curettage (D&C) procedures or infections

hpyerprolactinemia (glactorrhea)

This hypersecretion of prolactin suppresses GnRH, low LH and FSH, and impairs gonadal steroidogenesis This can cause amenorrhea with breast development and normal mullerian structures with hypoestrogenism. The end result is menstrual disturbances and galactorrhea

MRI

This imaging modality is recommended for the hypothalamic/pituitary area in cases of hypogonadotropic hypogonadism, causing primary amenorrhea with sexual infantilism Patients also have low FSH and LH and low estrogen. Screening for other pituitary hormones is indicated.

mullerian anomalies

This is a classification of primary amenorrhea with breast development but these anomalies possible causes include androgen insensitivity (46, XY), normal female karyotype (46, XX), imperforate hymen, transverse vaginal septum, cervical agenesis, and mullerian agenesis and/or dysgenesis These causes are distinguished by serum testosterone level and karyotype

sexual infantilism

This is a classification of primary amenorrhea without evidence of secondary sexual characteristics. This is characterized by absence of gonadal hormone secretion Possible causes include hypogonadotropic hypogonadism, hypergonadotropic hypogonadism, and 17-hydroxylase (P450c17) deficiency

primary amenorrhea

This is defined as NO menses by age 16. This should consider evaluation if no menses by age 15 or within (2) 3 years of thelarche, or lack of breast development by age 13 (14)

oligomenorrhea

This is defined as bleeding less frequently than every 35 days

secondary amenorrhea

This is defined as no menses for 3-6 months, or the duration of 3 menstrual cycles in menstruating women

hypogonadotropic hypogonadism

This is on the differential diagnosis for primary amenorrhea with sexual infantilism. This is when the hypothalamus does not secrete GnRH in its normal pulsatile fashion, disrupting the loop between hypothalamus and pituitary FSH and LH secretion does not occur, therefore ovaries are not stimulated to secrete estradiol and secondary sexual maturation is delayed The most common cause is constitutional or physiologic delay.

pregnancy

This is the most common cause of amenorrhea. Other causes include hypothalamic-pituitary-ovarian dysfunction and alteration of the genital outflow tract

constitutionally delayed puberty

This is the most common cause of hypogonadotropic hypogonadism resulting in primary ammenorrhea with sexual infantilism You want to exclude other serious causes before diagnosing with this, therefore this diagnosis is one of exclusion. If patient presents with anosmia/hyposmia, think Kallmann syndrome

gonadal agenesis

This is the most common cause of primary amenorrhea, resulting in hypergonadotropic (elevated FSH) hypogonadism (low estrogen) This can be characterized as Turner Syndrome (45, XO) or pure form (46XX or 46XY). Usually, there are NO signs of secondary sexual characteristics If Y chromosome is present, there is a risk of gonadoblastoma or dysgerminoma, so all patients with hypergonadotropic sexual infantilism should have karyotype

hypoestrogenism

This may be indicated in cases amenorrhea with breast development and normal mullerian structures with a negative progesterone challenge Differential diagnosis includes pregnancy (always do B-HCG), hypothalamic/pituitary dysfunction (low FSH and PRL), premature ovarian failure (high FSH and normal PRL), and hyperprolactinemia (high PRL and low FSH)

transverse vaginal septum

This mullerian abnormality shows an obstruction visible on MRI scan. Clinical features include cyclic lower abdominal pain without menses (amenorrhea), hematometra (retention of blood in uterus), and decreased fertility potential

imperforate hymen

This mullerian abnormality shows hematocolops on abdominal ultrasound Clinical features include bulge at introitus, and cyclic pain with absent vaginal bleeding (amenorrhea)

mullerian agenesis

This refers to absence of cervix, uterus, fallopian tubes and upper vagina. This can be seen in 46XX females with primary amenorrhea with breast development Rectal exam and ultrasound demonstrate absence of uterus.

Mayer-Rokitansky-Kuster-Hauser syndrome

This syndrome is an example of Mullerian agenesis/dysgenesis, where there is an absence of cervix, uterus, tubes and upper vagina Ovarian function is normal since those are not of Mullerian origin, so all secondary sexual characteristics are normal (breast development). IV pyelogram or other renal imaging is indicated since renal abnormalities are often associated with mullerian agenesis/dysgenesis

progestin challenge test

This test is given first to see if amenorrhea is disorder of outflow tract or uterus Patients are given progesterone in oil 200mg im and provera 10mg/day for 5 days. if positive withdrawal bleed, patients have normal endogenous estrogen, intact ovarian axis (CNS), and reactive endometrium If negative withdrawal bleed, repeat test with E-P

gonadal resection

This treatment is considered for androgen insensitivity syndrome once puberty is complete, since the misplaced gonads are at risk of neoplasia Additional treatments include counseling and creation of neovagina if desired

pregnancy test

You should always perform this test in cases of amenorrhea (or oligomenorrhea) with breast development and normal mullerian structures, whether the amenorrhea may be primary or secondary Additional diagnostic features include age of thelarche, pubarche, menarche, weight change, strenuous exercise, diet, sexual activity, and vasomotor systems Helpful labs include UCG/HCG and progestin challenge test (maybe estradiol). If there is negative progesterone challenge, may be hypoestrogenism, uterine defect or pregnancy