Primary Amenorrhea
A patient with primary amenorrhea has breast tissue and a uterus. What tests would you do for work-up?
1. hCG - always make sure not pregnant 2. Progesterone Withdrawal Bleed (Provera) - has a High false positive rate but *confirms patent outflow tract.* 3. FSH/LH 4. Prolactin, TSH
Genetic Defect in Turner's Syndrome
45 X karyotype due to *non-disjunction during meiosis* or mosaicism
Pathophysiology of AI
46 XY Patient has properly working gonads so AMH is produced resulting in absence of Mullerian structures. However, the testosterone and androgens that are produced can not interact and cause an effect with the androgen receptor. This results in increased LH and testosterone levels which is then peripherally aromatized to estrogens which stimulate development of breast tissue. Breast tissue development ramps up at puberty since the amount of androgens increases. Since the androgen receptor is abnormal, there is *scant axillary and pubic hair* since terminal hair growth is dependent on androgen receptor activity. Increased risk of gonadal malignancy since have Y chromosome - *remove gonads after puberty (21-22) once secondary sex characteristics are developed*. - *Must put on standard hormone therapy (estrogen) after removal. Do not need progesterone b/c they do not have uterus.*
5-Alpha Reductase Deficiency
AKA "Penis at 12 Syndrome" = ambiguous genitalia until puberty, then penis develops due to increased testosterone levels. Decreased dihydrotestosterone *Autosomal recessive* 46 XY males have severe hypospadias and variable development of the vagina. NO Müllerian structures. Most have such little virilization at birth that they are raised as females. However there is virilization at the time of puberty -so much so that they are often raised as males following puberty. At birth, Wolffian structures are normally formed as they develop under the influence of testosterone. External genitalia and the structures derived from the urogenital sinus are not virilized because these structures respond to dihydrotestosterone, not testosterone. At puberty, testosterone levels increase to the normal range. However, the ratio of testosterone to dihydrotestosterone is greatly increased.
Swyer's Syndrome
AKA *46XY Gonadal Dysgenesis* Ranges from complete with female phenotype to various degrees of undervirilization. *Increased risk for gonadoblastoma & dysgerminoma = must remove gonads ASAP* (not after puberty) as they are more likely to develop malignancy earlier than AI) Labs: elevated gonadotropins, low test, and 46 XY karotype (15 % mutations in SRY gene)
Mullerian Agenesis
AKA Mayer-Rokitansky-Kuster-Hauser (MRKH) Syndrome *46 XX*. Have normal secondary sex characteristics and normal T for a female, the Mullerian tract just was not able to grow. *Associated with skeletal and urinary anomalies = MUST GET MRI*
A patient with primary amenorrhea has breast tissue but no uterus. What tests would you do for work-up?
DDX = AI or Mullerian Agenesis - Karyotype (AI = 46, XY) - Pubic hair assessment (AI will have scant pubic hair) - Testosterone level (high to nl in AI) - +/- Pelvic US/MRI Usually get MRI when pt has Mullerian Agenesis since it is associated with renal and skeletal anomalies.
Swyer's Syndrome - Etiology
Deletion of the short arm of chromosome Y, SRY (sex-determining region). This is the TDF or testis determining factor gene. The presence of SRY determines male versus female development Will be raised as females and must be given estrogen/progesterone HT.
Turner's Syndrome
Deletion or rearrangement (*nondisjunction*) of the X chromosome that results in Gonadal Dysgenesis. Early ovarian failure or nonfunctioning *streak gonads*. Require estrogen replacement - Start at low doses combined with growth hormone = higher adult height and better secondary sexual characteristic development. - Best to start earlier Monitor thyroid function, check BP, and watch for celiac dz
A patient with primary amenorrhea has no breast tissue development but has a uterus. What tests would you do for Work-Up?
FSH/LH Karyotype CT/MRI of head (for hypothalamic/pituitary tumors) BP (HTN characteristic of 17a Hydroxylase)
Signs of Turner's Syndrome
High arched palate Low-set prominent ears Cubitus valgus Shield chest Cardiovascular abnormalities (particularly coarctation of the aorta). Lymphedema/webbed neck Normal intellectual development but can have difficulty with math and spatial-temporal relationships.
How do you classify the different causes of primary amenorrhea?
If the pt does *NOT have ambiguous genitalia*, divide the causes into 4 categories by answering two questions: - Do they have breast development? Indicates (+) estrogen production - Is there a uterus present? Indicates no AMH production = no functional Sertoli cells.
A patient with primary amenorrhea has no breast tissue development and no uterus. What tests would you do for Work-Up?
Karyotype FSH/LH Testosterone Level Estradiol Level Pelvic/genital exam get BP Assess pubic hair and tanner staging.
Complete Androgen Insensitivity
Most common form of male pseudohermaphroditism (DSD). Results from a *defect in the androgen receptor*. Androgens are produced but they are unable to initiate any effects. *Karyotype = 46, XY* Phenotypically females (breasts but NO uterus) Pt has intra-abdominal or inguinal gonads, and appear to have normal external female genitalia at birth. *X-Linked inheritance*
Primary Amenorrhea - Definition
Never getting a period. Secondary amenorrhea = has had previous periods but now they have stopped. Delayed puberty: No thelarche (breast bud) by 13; no menarche by 15 Sometimes defined as absent menses at 14 in absence of secondary sexual characteristics or 16 with secondary sexual characteristics.
Swyer's Syndrome Karyotype and Pathophysiology
Normal female external and internal genitalia Gonadal dysgenesis ocurred prior to its production of AMH. This means there is a uterus since no AMH could be produced. XY karyotypes with female phenotype Requires gonadectomy to prevent virilism and high malignant neoplasia risk
Most Common Causes of Primary Amenorrhea
"XMAS" Mneumonic X = Turner's (43%) M = Mullerian Agenesis (14%) A = Androgen insensitivity (1%) S = Swyer's Syndrome (1%)
A patient with primary amenorrhea has breast tissue and a uterus. What are common causes?
(+) Breasts = estrogen production (+) Uterus = no AMH production Outflow Obstruction Would work-up like Secondary Amenorrhea -pregnancy -endocrine/hypothalamic/pit -ovarian: anovulation, PMOF
A patient with primary amenorrhea has breast tissue but no uterus. What are common causes?
(+) Breasts = estrogen production (-) Uterus = AMH production Androgen Insensitivity (46, XY) Mullerian Agenesis (MRKH, 46 XX)
A patient with primary amenorrhea has no breast tissue development but has a uterus. What are common causes?
(-) Breasts = no estrogen production (+) Uterus = no AMH production Hypergonadotropic: - Gonadal dysgensis (Turners) - Swyers (46XY, lose gonadal production prior to AMH production so you do not get gonadal AMH secretion which defaults to the growth of a uterus) - Pure XX Hypogonadotropic: -Kallmans -Physiologic/constitutional delay
A patient with primary amenorrhea has no breast tissue development and no uterus. What are common causes?
(-) Breasts = no estrogen production (-) Uterus = AMH production XY Enzyme Deficiencies: - 17,20 desmolyase Deficiency - 17 alpha hydroxylase deficiency - 17B hydroxysteroid dehydrogenase deficiency - 5 alpha reductase deficiency
What is the single most common chromosomal abnormality in spontaneous abortions?
Turner's Syndrome 45 X0 or 46,XX 45 X0 Mosaic Only 3% of Turner fetuses survive to term
Why do Turner's Syndrome patients have "streak ovaries"?
due to the accelerated atresia of the primordial germ cells. When this atresia is completed prior to purberty, it results in gonadal failure and lack of pubertal development Atresia may not be complete until after puberty, in which case normal development may occur. These patients may have normal fertility in their early reproductive years, although rare. Usually better prognosis with mosaicism.