Follicle-Stimulating Hormone (FSH)

Age-specific, gender-specific, and, for women, menstrual cycle phase–specific reference intervals have been established for follicle-stimulating hormone (FSH). (However, depending on the laboratory method used, variations in values can occur.)

Normal findings for FSH (IU/L)

Adult ^[1]

Male: 1.42-15.4

Female:

• Follicular phase: 1.37-9.9
• Ovulatory peak: 6.17-17.2
• Luteal phase: 1.09-9.2
• Postmenopause: 19.3-100.6

Child (age 1-10 years) ^[1]

Male: 0.3-4.6

Female: 0.68-6.7

Conditions associated with increased FSH include primary hypogonadism, either congenital or acquired:

• Klinefelter syndrome ^[2]  

• Turner syndrome

• Other chromosomal disorders

• Cryptorchidism

• Disorders of androgen biosynthesis

• Sertoli-cell-only syndrome

• Androgen insensitivity syndrome

• FSH receptor mutations

• Myotonic dystrophy

• Infection (eg, mumps, orchitis)

• Radiation

• Medication (antineoplastic agents such as cyclophosphamide, chlorambucil, cisplatin, carboplatin, glucocorticoids, Ketoconazole, suramin)

• Chemicals (eg, dibromochloropropane)

• Trauma

• Testicular torsion

• Chronic systemic disease (eg, cirrhosis, chronic renal failure, HIV disease)

• Ovarian failure ^{[3, 4]}

• Pituitary gonadotroph macroadenomas

Conditions associated with decreased FSH include the following secondary or tertiary causes of hypogonadism, either congenital or acquired:

• Isolated idiopathic hypogonadotropic hypogonadism (GnRH deficiency)

• Kallmann syndrome 

• Idiopathic hypogonadotropic hypogonadism associated with mental retardation (eg, Prader-Willi syndrome)

• Craniopharyngioma

• Combined pituitary hormone deficiency

• Mass lesions (eg, pituitary adenomas, cysts, metastatic disease)

• Hypothalamic/pituitary surgery or radiation

• Infiltrative disease (eg, sarcoidosis, hemochromatosis, histiocytosis)

• Meningitis (especially tuberculous meningitis)

• Pituitary apoplexy

• Head trauma

• Glucocorticoid excess (endogenous or exogenous)

• Hyperprolactinemia

• Primary hypothyroidism

• Sex steroid–secreting tumors

• Anorexia nervosa

• Congenital adrenal hyperplasia

• Chronic systemic disease (eg, cirrhosis, chronic renal failure, HIV disease)

Preferred specimen and acceptable tubes:

• Serum (red top tube, SST)
• Plasma (green top tube - sodium heparin, ammonium heparin, lithium heparin; PST)

Specimen volume: 0.5 mL plasma or serum (0.1 mL minimum volume)

Specimen stability: 

• Centrifuge specimens and remove serum or plasma from the cells within 2 hours of the collection
• Store at room temperature for 8 hours, or refrigerate at 2-8 degrees Celsius (36-46 degrees Fahrenheit) up to 5 days. 
• If assays are not completed within 48 hours, or the separated sample is to be stored beyond 48 hours, samples should be frozen at -20 degrees Celsius or colder. Frozen samples should be thawed only once. Analyte deterioration may occur in samples that are repeatedly frozen and thawed.

Sample collection

Because of the cyclic and circadian variations in the secretion of gonadotropins, a meaningful evaluation of FSH and LH requires either testing of a pool of blood specimens collected 20-30 min apart or average the hormone measurements of multiple blood samples collected 20-30 min apart.

Related tests:

• Total estrogens
• Estradiol
• Luteinizing hormone
• Testosterone
• Progesterone

Usually, for a better and rapid evaluation of hypothalamic-pituitary-gonadal axis, both FSH and LH are evaluated together in the same sample and in the same time and most of the modern assays are using cocktails of antibodies for both FSH and LH, allowing their concurrent evaluation.

Measurement of FSH

There are 2 major ways in which FSH is currently evaluated: radioimmunoassay (RIA) and chemiluminescence immunoassays.

In the RIA, endogenous FSH present in the sample is competing with iodine radiolabeled FSH for a limited amount of FSH-specific antibodies (“competitive assay”). The measured signal is inversely proportional with the amount of TSH present in the sample.

The chemiluminescence assay is using two antibodies (“sandwich immunoassay”). The “capture antibody” is usually binding the alpha subunit of FSH, while the “detection antibody” is always binding within the FSH-specific beta-subunit. The measured signal is directly proportional with the amount of FSH present in the sample. The chemiluminescence assay is significantly more sensitive than RIA. ^[3]  

As all immunoassays, these assays are prone to specific interferences, especially heterophilic antibodies. Hook effect is rarely seen. Interferences from other hormones with similar biochemical structure (eg, LH, TSH, hCG) and from free alpha subunits produced by some pituitary tumors were eliminated by using antibodies specifically directed against beta-subunit epitopes of FSH. However, epitope specificity was not yet achieved, and intense efforts are placed into standardization of the FSH assay. ^[5]

Measurement of FSH in urine

Because of the cyclic and circadian variations in the secretion of gonadotropins, it is difficult to overcome the issue of detection sensitivity using randomly collected blood samples, especially in children and prepubertal teens. Therefore, more and more pediatric endocrinologists support the idea of FSH and LH evaluation 3-hour urine collection. The kidneys integrate the episodic secretion of these hormones and the urine samples can be further concentrated, so the issue of detection sensitivity and variability can be overcome. ^[5]  

In women with PCOS, the concentration of FSH is low relative to the concentration of LH, with an increased ratio of LH to FSH. A ratio LH to FSH greater than 2.5 is often used for the diagnosis of PCOS. ^[6]

Description

The anterior pituitary gland produces two gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

FSH (see the image below) is a glycoprotein secreted by the anterior pituitary in response to gonadotropin-releasing hormone (GnRH), which, in turn, it is released by the hypothalamus.

Follicle stimulating hormone, beta polypeptide.

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Structurally, FSH and LH are composed of an alpha and a beta subunits. While alpha subunit is identical between gonadotropins TSH and hCG, the specific beta subunit confers the unique biologic activity. Upon release in circulation, FSH binds to G-protein coupled receptors in the testicular Sertoli cells and ovarian granulosa cells. Through this, FSH promotes spermatogenesis and secretion of inhibins in males, while in females, it stimulates the proliferation of the granulosa cells, development of a dominant follicle, expression of LH receptors, and secretion of estrogen and inhibins. In their turn, inhibins provide feedback centrally to the hypothalamus, and, in this way, they are also inhibiting the secretion of FSH. Together, these hormones and target organs form the “hypothalamic-pituitary-gonadal axis." Therefore, FSH is essential for reproduction in males and females. ^[5]  

The hypothalamic-pituitary-gonadal axis in men and women.

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Conditions related to LH and FSH abnormalities can be caused by pathology of either the hypothalamus or pituitary. Careful analysis of the presenting problem, the patient’s overall health, and the hormonal profile is often necessary to determine the cause of FSH abnormality and, thus, the most appropriate treatment. ^{[5, 7, 8]}

Assessment of FSH, LH, and additional hormones (eg, sex steroids, prolactin, thyroid hormones) is useful in evaluation of hypogonadism, delayed puberty, infertility, polycystic ovarian syndrome (PCOS), amenorrhea, and hypothalamic-pituitary dysfunctions.

Indications/Applications

Indications for testing of FSH include the following:

• Evaluating menstrual irregularities (including anovulatory bleeding)

• Evaluating suspected hypogonadism

• Evaluating precocious puberty

• Predicting ovulation

• Evaluating infertility

• Evaluating pituitary disorders