Follicle-Stimulating Hormone Abnormalities

Follicle-stimulating hormone (FSH) abnormalities are divided into 2 major groups (low and high), depending on FSH levels.

Causes of low FSH level (hypogonadotropic hypogonadism or secondary hypogonadism)

See the list below:

• Congenital: Sexual differentiation is normal. In men, phallic development may be subnormal, resulting in a micropenis. Pubertal development is diminished or even absent, depending on the degree of gonadotropin deficiency.

  • Isolated idiopathic hypogonadotropic hypogonadism: This usually results from GnRH deficiency, with absence of any other abnormalities. Mutations are shown in the image below. FSH and LH levels are low. ^[4]

    Human G protein-coupled receptor 54 (GPR54) receptor model. Mutations identified in patients with idiopathic hypogonadotropic hypogonadism are indicated.

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  • Kallmann syndrome: This is characterized by hypogonadotropic hypogonadism and 1 or more nongonadal congenital abnormalities, including anosmia, red-green blindness, midline facial abnormalities (eg, cleft palate), urogenital tract abnormalities, and neurosensory hearing loss. Hypogonadism in this syndrome is a result of deficient hypothalamic secretion of GnRH. Most cases are sporadic, but familial cases also occur. It is caused by mutations in the KAL gene. ^[5] Other mutations have been described, such as FGFR1 (KAL2), GPRS54, PROK-2, PROKR-2, CHD-7, and FGF-8. ^[6] See the image below.

    This is a frequently sampled serum luteinizing hormone (LH) profile in a male patient with Kallmann syndrome (KS), compared with that in a healthy individual. A lack of LH pulsatility is seen in the former.

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  • Idiopathic hypogonadotropic hypogonadism associated with intellectual disability: Several syndromes (eg, Prader-Willi syndrome) have been described in which hypogonadotropic hypogonadism is associated with retardation and other abnormalities, including obesity.

  • Craniopharyngiomas: These tumors arise from remnants of the Rathke pouch, which is the diverticulum of the roof of the embryonic oral cavity that normally gives rise to the anterior pituitary. Craniopharyngiomas are congenital malformations present at birth and gradually grow over the years. Approximately 75% arise in the suprasellar region. The most common presentation is due to increased intracranial pressure, including headaches and visual-field defects. A study by Zhang et al using the Surveillance, Epidemiology, and End Results (SEER) database found bimodal incidence peaks for craniopharyngiomas, with one peak for ages 20 years and younger and another for ages 40-65 years. ^[7]

  • Combined pituitary hormone deficiency: This results from a rare mutation in the gene encoding a transcription factor (PROP1), which is necessary for the differentiation of a cell type that is a precursor to somatotroph, lactotroph, thyrotroph, and gonadotroph cells, thus resulting in deficiencies in prolactin, thyroid-stimulating hormone (TSH), growth hormone (GH), FSH, and LH. A study by Otto et al found that of 83 patients with childhood-onset isolated GH deficiency, 37 (44.6%) developed combined pituitary hormone deficiency over a median 5.4-year follow-up, with FSH and LH deficiencies having a prevalence of 38% in these patients. ^[8]

  • Fertile eunuch syndrome: This is thought to represent an incomplete form of GnRH deficiency in men, in which an isolated and partial LH deficiency is present with low testosterone and normal FSH levels, resulting in preservation of spermatogenesis.

  • Abnormal beta subunit of LH: This is a rare mutation in the LH beta subunit gene.

  • Abnormal beta subunit of FSH: This is a rare mutation in the gene for the beta subunit of FSH, resulting in a low FSH level. This condition is encountered only in women but has been studied in male mice in which the FSH beta subunit gene has been knocked out. These mice have oligospermia but are fertile. ^[9]

• Acquired: This can be caused by any disease that affects the hypothalamic-pituitary axis, impairing the secretion of GnRH, FSH, or LH.

  • Mass lesions: These include pituitary adenomas (as shown below), cysts, and metastatic cancer to the sella (breast in women, lung and prostate in men). These masses may cause temporary or permanent damage by extrinsic compression of pituitary cells. Hypothalamic tumors may lead to delayed puberty, hypogonadism, and obesity, originally called Fröhlich syndrome or adiposogenital dystrophy. The presence of obesity indicates that the appetite-regulating regions of the hypothalamic have been damaged.

    Magnetic resonance imaging (MRI) scan of pituitary macroadenoma.

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  • Hypothalamic/pituitary surgery: If sufficient normal tissue is excised inadvertently, symptomatic hypogonadism may ensue initially, followed by dysfunction of other pituitary cells.

  • Hypothalamic/pituitary radiation: This may lead to multiple hormonal deficiencies, including FSH and LH.

  • Infiltrative lesions: Hemochromatosis, sarcoidosis, histiocytosis, and lymphoma can cause hypogonadism by involving the hypothalamic/pituitary region.

  • Lymphocytic hypophysitis: This is characterized by lymphocytic infiltration and destruction of the pituitary cells. Thought to be autoimmune in nature, lymphocytic hypophysitis is an uncommon disorder that usually occurs in women, often in the postpartum period. However, cases have also been described in men.

  • Infections: Meningitis, especially tuberculous, is a rare cause of hypogonadism in the United States.

  • Pituitary apoplexy: This is a sudden and severe hemorrhage into the pituitary, which can result in varying degrees of hypopituitarism, excruciating headaches, visual changes, and altered mental status.

  • Trauma: Head trauma of sufficient severity to fracture the skull base can sever the hypothalamic-pituitary stalk, preventing GnRH from reaching the pituitary, thus decreasing FSH and LH release.

  • Glucocorticoid excess: Exogenous or endogenous (Cushing syndrome) glucocorticoid excess can lead to hypogonadotropic hypogonadism. Direct inhibition of testosterone secretion may also occur at the testicular level.

  • Hyperprolactinemia: This can result from a pituitary adenoma, renal or liver insufficiency, primary hypothyroidism, or some drugs (eg, neuroleptics). Hyperprolactinemia can suppress GnRH secretion through a central dopamine-related mechanism. In addition to hypogonadism, this condition can also manifest as galactorrhea and as gynecomastia in men.

  • Primary hypothyroidism: This can lead to hypogonadism through hyperprolactinemia. A low thyroxine (T4) level results in a high thyrotropin-releasing hormone (TRH) level, which stimulates prolactin secretion.

  • Critical illness: Surgery, myocardial infarction, or other illness can cause transient hypogonadotropic hypogonadism, with resolution upon recovery.

  • Excessive exercise: This can cause a functional hypothalamic hypogonadism in men, analogous to women with functional hypothalamic amenorrhea.

  • Sex steroid–secreting tumors: These may be adrenal, testicular, or ovarian in origin, or, they may result from adrenal rest tumors. The excessive amount of testosterone or estradiol can inhibit FSH and LH secretion.

  • Intentional (iatrogenic) secondary hypogonadism: Prolonged administration of high doses of anabolic steroids (by athletes) or GnRH analogs (for prostate cancer) can cause low FSH or LH levels. Recovery may take many months or years after cessation of the drug. Also, women who discontinue oral contraceptives may have post-pill amenorrhea; recovery of the gonadotropin axis may take up to a year.

  • Empty sella: This term refers to an enlarged sella turcica that is not entirely filled with pituitary tissue, either from a defect in the diaphragm sella (allowing cerebrospinal fluid pressure to enlarge the sella) or secondary to a mass that is removed by surgery, radiation, or infarction.

  • Pituitary infarction: This condition rarely occurs in males; but, when present, it primarily manifests in older patients with vascular insufficiency during coronary artery bypass surgery. In women, it can occur postpartum as Sheehan syndrome, usually after substantial blood loss during childbirth. This condition manifests as partial or complete hypopituitarism, depending on the hormonal deficiencies; a low FSH or LH level causing amenorrhea is the most frequent cause.

  • Chronic systemic diseases: Cirrhosis, chronic renal failure, and AIDS may lead to hypogonadism, which has a dual mechanism, ie, primary and secondary.

  • Anorexia nervosa: In women, significant weight loss, up to 10% below the ideal body weight, may lead to functional hypothalamic amenorrhea.

  • Congenital adrenal hyperplasia: This is due to 21-hydroxylase deficiency or rarely to 11-hydroxylase deficiency; both lead to high levels of androgens, which can lower FSH and LH levels.

  • Acute alcohol ingestion: This may lead to primary or secondary hypogonadism.

  • Idiopathic: No cause is identified in some men and women with acquired secondary hypogonadism. The cause may be autoimmune in origin.

  • Type 2 diabetes: Research has indicated that low concentrations of testosterone, LH, and FSH are prevalent in patients with type 2 diabetes who are obese. ^[10] Evidence suggests that inflammation may play an important part in this phenomenon.

Causes of high FSH level

Primary hypogonadism: This can be congenital or acquired

• Congenital: Sexual differentiation in men may vary from pseudohermaphrodism to a male with only a micropenis and lack of full pubertal development. In women, sexual differentiation is normal but puberty is delayed or absent.

  • Klinefelter syndrome: This syndrome is the most common congenital abnormality causing primary hypogonadism in men. The typical genotype is 47,XXY. The clinical presentation includes infertility, small and firm testes, and low testosterone with high FSH and LH levels (see the image below). Males with Klinefelter syndrome usually present in their prepubertal years. ^{[11, 12, 13]}

    Adolescent male with Klinefelter syndrome who has female-type distribution of pubic hair, as well as testicular dysgenesis.

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  • Other chromosomal abnormalities: These result in testicular hypofunction; they include the 46,XY/XO and the 47,XYY karyotypes.

  • Mutation in the FSH receptor gene in men and women: This mutation is rare and results in low sperm count with a high FSH level in men. Women present with amenorrhea and elevated FSH. ^[14]

  • Cryptorchidism: This refers to undescended testes, as in the image below. The clinical consequences depend on whether 1 or both testes are cryptorchid. If only 1 testis is affected, the sperm count is subnormal in almost 30% of patients and the FSH level is slightly elevated. If both testes remain undescended, the sperm count is usually severely subnormal with a high FSH level and low serum testosterone. A study by Rohayem et al indicated that in males with undescended testes, a positive correlation exists between the age of correction and levels of FSH and LH. ^[15]

    Hypoplastic right hemiscrotum in a patient with an undescended right testis.

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  • Disorders of androgen biosynthesis: This involves mutations of the genes that encode the enzymes necessary for testosterone biosynthesis. They result in incomplete virilization, low sperm count, low testosterone level, and high LH and FSH levels.

  • Sertoli-cell-only syndrome: The characteristic features are complete, or almost complete, absence of germ cells in all seminiferous tubules. Leydig cells are only mildly impaired. These men have azoospermia with high FSH levels. LH and testosterone levels are normal. The cause has not been identified, but it is thought to be a congenital absence or early neonatal loss of the germ cells.

  • End organ resistance to androgens: This is due to androgen receptor defects. In its complete form, it is called testicular feminization. Affected individuals are genetic males but phenotypic females. The testes are located in the labia, the inguinal canal, or the abdomen. Testosterone and LH levels are high. The FSH level is normal or slightly increased.

  • Turner syndrome: This is 45,X gonadal dysgenesis in women. It is characterized by short stature, sexual infantilism, and distinctive features. These women have primary amenorrhea and infertility. They have distinctive facies, including micrognathia, epicanthal folds, and prominent low-set ears. The neck is short and broad with webbing in 25-40%. They can have associated cardiac, renal, or skeletal abnormalities. ^{[16, 17]}

  • Myotonic dystrophy: This is an autosomal dominant disorder that leads to muscle atrophy accompanied by hypogonadism manifesting as small testes and decreased sperm production. The FSH level is high in most of these patients; approximately half have low testosterone and high LH levels.

• Acquired

  • Infections: The most common is mumps orchitis. The seminiferous tubules are almost always severely affected, often resulting in infertility, especially with bilateral testicular involvement. The Leydig cells may also be damaged, resulting in decreased testosterone production with high LH levels.

  • Radiation: This mostly damages the seminiferous tubules or the ovaries. The degree of damage is proportionate to the level of radiation exposure.

  • Antineoplastic agents: As with cyclophosphamide, chlorambucil, cisplatin, and carboplatin may decrease the sperm count by destruction of the seminiferous tubules. Less commonly, testosterone secretion also declines. Recovery may occur over the long-term. Similarly, in women, chemotherapy may lead to ovarian failure.

  • Chemicals: Chemicals such as dibromodichloropropane can decrease spermatogenesis.

  • Glucocorticoids: These can lead to hypogonadism via inhibition of the pituitary and testes.

  • Ketoconazole: This is an antifungal drug that inhibits testosterone biosynthesis.

  • Suramin: This is an antiparasitic drug that can block testosterone synthesis by the Leydig cells.

  • Trauma: Injuries can be sufficiently severe to damage both seminiferous tubules and Leydig cells.

  • Testicular torsion: Torsion of more than 8 hours duration may lead to a low sperm count. Even if the torsion involves only 1 testis, both testes may be damaged; the mechanism is not known.

  • Chronic systemic diseases: Cirrhosis, chronic renal failure, and AIDS may lead to hypogonadism, both primary and secondary. Bilateral aortofemoral anastomosis in men may lead to decreased blood supply to the testes, predominantly affecting the seminiferous tubules.

  • Ovarian failure: Failure occurs when the supply of oocytes and surrounding follicles is depleted. This usually happens at approximately age 50 years in American women during the course of normal menopause. Premature depletion of oocytes prior to age 40 years is called premature menopause or premature ovarian failure. The lack of ovarian function leads to absolute estrogen deficiency, endometrial atrophy, and the absence of menstruation. Loss of negative feedback of estradiol on the hypothalamus and pituitary and the loss of inhibin result in high FSH levels.

  • Autoimmune damage: This is due to antisperm antibodies. It may be part of an autoimmune polyglandular syndrome.

  • Idiopathic: Many men and women with primary hypogonadism have idiopathic disease, and the cause is never identified. The cause may be autoimmune in origin.

  • Gonadotroph adenomas: These are the most common pituitary macroadenomas. They usually do not cause a recognizable clinical endocrine syndrome. They manifest as visual impairment, headaches, and deficiency of pituitary hormones due to compression of nonadenomatous pituitary cells by the macroadenoma. The gonadotroph adenoma itself can oversecrete FSH, LH, or one of the subunits (alpha or beta).

Frequency

International

The frequency depends on each disease and its manifestation of high or low follicle-stimulating hormone levels. Refer to the appropriate articles for prevalence rates.

An Israeli study, by Gruber et al, found that between 2009 and 2016, the incidence of new diagnoses of primary ovarian insufficiency (ie, 4 mo or more of amenorrhea linked to menopausal levels of FSH) was 4.5 per 100,000 person-years, versus 2.0 per 100,000 person-years between 2000 and 2008. ^[18]

Mortality/Morbidity

The resulting morbidity and mortality are usually related to the conditions that cause the alterations in follicle-stimulating hormone secretion.

A cross-sectional observational study by Giovanelli et al suggested that in males, an excess of FSH negatively impacts bone mass. Following adjustment for potential confounders, the investigators found that compared with males with hypogonadotropic hypogonadism, men with non–Klinefelter syndrome hypergonadotropic hypogonadism (non-KS-Hyper-H) demonstrated significantly lower lumbar spine bone mineral density (BMD). There was also a tendency toward lower femoral neck BMD values in males with non-KS-Hyper-H compared with those with hypogonadotropic hypogonadism. In addition, it was determined that males in the study with Klinefelter syndrome had a significantly lower lumbar spine BMD than did those with non-KS-Hyper-H. ^[19]