LabMed

Primary Amenorrhea due to Pure Gonadal Dysgenesis/Agenesis

At a Glance

Amenorrhea is the absence of menstrual blood flow. Primary amenorrhea should be considered in any patient with secondary sex characteristics who has not experienced periodic menstruation by 16 years of age or 5 years after breast development. Patients who have not developed secondary sex characteristics, especially the absence of breast development, and have not established periodic menstruation by 13 years of age should also be worked up for primary amenorrhea.

Pure gonadal dysgenesis (streak gonads) occurs in phenotypic females with normal chromosomal make-up. Patients with pure gonadal dysgenesis/agenesis are often short in stature with primary or secondary amenorrhea. Patients may have either 46,XX (Perrault syndrome and others) or 46,XY karyotypes (Swyer syndrome).

Primary amenorrhea occurs in patients with pure gonadal dysgenesis because of absent or limited ovarian function due to inappropriate development. Streak gonads are unable to produce estrogens and/or androgens, resulting in minimal to no development of secondary sex characteristics. Adrenal androgens may induce production of pubic hair, but patients will have minimal breast development.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

The work-up for primary amenorrhea begins with a careful history and physical exam to look for anatomical defects, development of secondary sexual characteristics, and/or a personal or family history of delayed puberty, short stature, and/or amenorrhea. Physical exam of patients with primary amenorrhea due to pure gonadal dysgenesis (PGD) may reveal a small woman with normal, unambiguous female genitalia with minimal development of secondary sex characteristics (pubic hair, but no breast development). These patients may have a family history of infertility, short stature, sensorineural deafness, ataxia, mild mental retardation, or gonadoblastoma.

Without ovaries, these patients are unable to conceive, unless they undergo IVF. Thus, the laboratory work-up for primary amenorrhea due to gonadal dysgenesis should include measurement of human chorionic gonadotropin (hCG) to rule out pregnancy only in patients that have undergone IVF. If the patient is not pregnant, the patient should undergo imaging studies to detect the presence or absence of a uterus and gonads.

Patients with PGD have streak gonads with a normal prepubescent uterus. Prior to further work-up for PGD, patients with a detectable uterus should be evaluated for hypothyroidism and prolactinemia. A high thyroid stimulating hormone (TSH) result suggests the amenorrhea is due to primary hypothyroidism and should be followed with fT4 analysis. A reduced fT4 confirms hypothyroidism. An elevated prolactin result should prompt a physician to perform an MRI in search of a pituitary adenoma. Prolactin inhibits gonadotropin function, thus, causing amenorrhea in nursing mothers and patients with prolactinomas.

Patients with normal TSH and prolactin should be evaluated for gonadotropic function by measuring Luteinizing hormone (LH) and Follicle stimulating Hormone (FSH). Although suggested by the lack of secondary sex characteristics, estrogen measurements may also be helpful. Low estrogen concentrations are expected in patients with PGD.

Because of day-to-day variability in estrogen concentrations, the progestin challenge test is often preferred to establish estrogen reserves and/or etiology of primary amenorrhea in patients with an intact uterus and some secondary sex characteristics. Theoretically, if progesterone is given to an estrogen primed uterus, withdrawal bleeding (menses) will occur. Progesterone is given orally for up to 1 week. Bleeding should occur within 1 week of progesterone withdrawal if the woman’s ovaries have produced enough estrogen (>40 pg/mL serum) to prime her uterus. A woman with PGD should not experience bleeding 1 week after progesterone withdrawal.

High concentrations of FSH and/or LH combined with low estrogen concentrations or a failed progesterone challenge test are suggestive of primary ovarian failure. Ovarian failure often occurs in utero in patients with PGD and is confirmed with subsequent elevated FSH measurements.

Karyotyping is critical for the diagnosis of PGD in patients with primary amenorrhea, an intact uterus, and no ovaries (although streak gonads are often not seen on ultrasound) with confirmed ovarian failure. 46,XX or 46,XY karyotypes are associated with PGD. Laparoscopic evaluation and/or gonadal biopsy may be necessary to identify streak gonads.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

False-positive and false-negative urine pregnancy results may occur and result in a misdiagnosis. False-negative results occur if urine is too dilute. To ensure an appropriate urine specimen, perform urine pregnancy testing on first morning voids and check the protein concentration by measuring the urine specific gravity and/or urine creatinine. False-negative results may also be caused by the variant effect.

This phenomenon occurs when high concentrations of hCG isoforms in urine (hCG beta core fragment) are not recognized by both antibodies in the assay. Instead, they interfere with one antibody and cause a false-negative result. One can test for the variant effect by diluting the urine sample and repeating the testing.

Prolactin is mildly elevated by stress, herpes simplex virus (HSV) infections in the chest wall, and numerous drugs, including dopamine agonists, proton pump inhibitors, antipsychotics (risperidone, phenothiazines, haloperidol), antihypertensives (methyldopa, reserpine, verapamil), estrogens, and illicit drugs (amphetamines, cannabinoids, opiates, etc). Any of these may lead to dysregulation of gonadotropins, amenorrhea, and infertility.

LH and FSH are episodically released from the pituitary, and concentrations may vary, depending on when they are measured during the day. First morning specimens are recommended. LH and FSH concentrations change throughout the menstrual cycle, even in amenorrheic patients. It is recommended to measure LH and FSH early in the follicular phase of the cycle if possible.

Concentrations of LH and FSH change dramatically during puberty. Results should be evaluated in the context of age and Tanner stage specific reference intervals. Drugs, such as anticonvulsants, clomiphene, and naloxone, may falsely elevate LH, whereas smoking, cimetidine, clomiphene, digitalis, and levodopa elevate FSH. Artificially low LH and FSH results may occur in patients taking oral contraceptives and hormone treatments. Phenothiazines reduce FSH concentrations, whereas digoxin decreases LH.

Estrogen can be measured by immunoassay or LC/MS/MS. Because immunoassays are imprecise at low concentrations, it is recommended that estrogen be measured by LC/MS/MS in men, children, and early Tanner stages. Estrogen concentrations vary throughout the menstrual cycle even in amenorrheic women, and should be measured in the early follicular phase of the cycle if possible. Chronic illnesses, such as anemia, hypertension, and liver and kidney diseases, affect estrogen concentrations.

Several estrogen containing drugs, such as birth control pills and hormone replacements, may interfere with the assays, causing falsely elevated results. Glucocorticoids, antibiotics (ampicillin and tetracycline), and phenothiazines may also cause false elevations in estrogen measurements. Clomiphene and oral contraceptives may reduce estrogen concentrations.

Patients with excess androgen concentrations may not respond to the progestin challenge test. Further, patients with obesity and/or severe stress may respond to the progestin challenge testing with withdrawal bleeding despite gonadal failure (false-negative results).

As is the case with many immunoassays, heterophilic antibodies can cause false-positive results. Therefore, caution should be taken when elevated hCG, TSH, prolactin, estradiol, LH, and/or FSH results do not match the clinical picture.

What Lab Results Are Absolutely Confirmatory?

Identification of mutations in the SRY, NR5A1 (SF1), DHH (46,XY), FSHR, or BNP15 (46,XX) genes in amenorrheic patients with a uterus, streak gonads, and a 46,XY or 46,XX karyotype or a mutation in the HSD17B4 gene in a patient with a uterus, streak gonads, deafness, and a 46,XX karyotype (Perrault syndrome) confirms the diagnosis.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Although detection of streak gonads on ovarian biopsy confirms PGD, its utility in patients with primary amenorrhea is questionable. In particular, pregnancies have occurred in karyotypic females (46,XX) with premature ovarian failure and no gonadal follicles noted on biopsy. Thus, in patients with primary amenorrhea, PGD must be differentiated from other causes of hypergonadotropic (high FSH and LH) hypogonadism (low estrogen).

Infectious and iatrogenic causes of primary ovarian failure should be ruled out by checking for a history of ovarian surgery, chemotherapy, or irradiation or past viral infection, such as AIDS or mumps.

Personal or family history of autoimmune disease, such as Addison’s, thyroid, DM I, SLE, rheumatoid arthritis, vitiligo, Crohn’s disease, and Sjogren’s syndrome, may suggest autoimmune destruction of the ovaries.

Detection of antiovarian antibodies in serum of patients with primary amenorrhea and ovarian failure is not recommended because of lack of correlation with disease state or onset.

Several enzyme deficiencies may lead to primary amenorrhea and ovarian failure, including cholesterol desmolase, 17α-hydroxylase, 17-20 desmolase, and aromatase enzymes. The most common, 17α-hydroxylase deficiency, is associated with elevated progesterone and 11-deoxycorticosterone concentrations combined with decreased 17α-hydroxyprogesterone (17-OHP), testosterone, estradiol, DHEA-S, and aldosterone. Markedly elevated progesterone and undetectable 17-OHP 1 hour after adrenocorticotrophic hormone (ACTH) stimulation confirms the diagnosis.

Although rare in patients younger than 40 years of age, gonadotropin secreting pituitary tumors should be ruled out if there are clinical signs of mass effect (headaches, visual field changes, etc.). The combination of MRI and thyroid releasing hormone (TRH) stimulation test identifies the majority of these patients.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Progesterone is elevated in pregnant women and those taking oral contraceptives.

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