Treatment for high FSH levels in males

Follicle-stimulating hormone (FSH) is a glycoprotein gonadotropin secreted by the anterior pituitary in response to gonadotropin-releasing hormone (GnRH) released by the hypothalamus. The pituitary gland also secretes luteinizing hormone (LH), another gonadotropin. FSH and LH are composed of alpha and beta subunits. The specific beta subunit confers the unique biologic activity. FSH and LH bind to receptors in the testis and ovary and regulate gonadal function by promoting sex steroid production and gametogenesis. [1]

In men, LH stimulates testosterone production from the interstitial cells of the testes (Leydig cells). FSH stimulates testicular growth and enhances the production of an androgen-binding protein by the Sertoli cells, which are a component of the testicular tubule necessary for sustaining the maturing sperm cell. This androgen-binding protein causes high local concentrations of testosterone near the sperm, an essential factor in the development of normal spermatogenesis. Sertoli cells, under the influence of androgens, also secrete inhibin, a polypeptide, which may help to locally regulate spermatogenesis. Hence, maturation of spermatozoa requires FSH and LH.

In women, LH stimulates estrogen and progesterone production from the ovary. A surge of LH in the midmenstrual cycle is responsible for ovulation, and continued LH secretion subsequently stimulates the corpus luteum to produce progesterone. Development of the ovarian follicle is largely under FSH control, and the secretion of estrogen from this follicle is dependent on FSH and LH. The granulosa cells of the ovary secrete inhibin, which plays a role in cellular differentiation.

FSH and LH secretion are affected by a negative feedback from sex steroids. Inhibin also has a negative feedback on FSH selectively. High-dose testosterone or estrogen therapy suppresses FSH and LH. Primary gonadal failure in men and women leads to high levels of FSH and LH, except in selective destruction of testicular tubules, with subsequent elevation of only FSH, as in Sertoli-cell-only syndrome. Similarly, any process leading to a low FSH level also simultaneously results in a low LH level, except in rare instances of isolated FSH deficiency or isolated LH deficiency in fertile eunuch syndrome.

Signs and symptoms of follicle-stimulating hormone abnormalities

In men presenting with low FSH levels leading to secondary hypogonadism or high FSH levels resulting from primary hypogonadism, the history reveals erectile dysfunction, decreased libido, infertility, and low energy.

In men presenting with high FSH levels due to a gonadotroph adenoma, symptoms result from the mass effect (eg, headaches, visual impairment, hormonal deficiencies). However, erectile dysfunction and infertility may occur secondary to low LH levels caused by compression of the normal gonadotroph cells.

In women with high FSH levels from a gonadotroph adenoma, symptoms are frequently due to mass effect (eg, headaches, visual changes, hypopituitarism). However, a high FSH level may also lead to ovarian hyperstimulation in premenopausal women, with multiple ovarian cysts [2] and a thickened endometrium; this leads to disturbed menstrual cycles, ie, oligomenorrhea or amenorrhea.

Diagnosis of follicle-stimulating hormone abnormalities

Perform additional laboratory studies in men presenting with low follicle-stimulating hormone (FSH) levels, including the following:

• LH and testosterone levels

• Prolactin levels

• Serum estradiol levels: This is performed to exclude an estrogen-secreting tumor (testes, adrenals) in men with low FSH levels and feminizing features, including gynecomastia

• Semen analysis: This is performed to assess fertility

In men presenting with high FSH levels, the underlying etiology is related to primary hypogonadism or a gonadotroph adenoma. Therefore, the following lab tests are indicated:

• LH and testosterone levels

• In patients with gonadotroph adenomas, other pituitary hormone levels must also be assessed because macroadenomas may induce hypopituitarism; serum TSH and free thyroxine (T4), morning cortisol and adrenocorticotropic hormone (ACTH), prolactin, and, occasionally, dynamic testing for growth hormone (GH) may be necessary

• Peripheral leukocyte karyotype: This is obtained in men with congenital primary hypogonadism to determine if Klinefelter syndrome is present

In women presenting with low FSH levels, additional testing should include determination of LH, estradiol, and prolactin levels. Thyroid disease should be excluded by measuring TSH and free T4. If hirsutism is present, serum testosterone and dehydroepiandrosterone sulfate (DHEAS) testing should be performed. Moreover, additional testing such as determination of the serum 17-hydroxyprogesterone level before and after ACTH stimulation may be performed if congenital adrenal hyperplasia is suggested.

In women with high FSH levels, the differential diagnosis is either ovarian failure or gonadotroph adenoma. The following points should be remembered:

• In women with ovarian failure, both FSH and LH levels rise; in women with gonadotroph adenomas, FSH levels are usually high, but LH levels remain within reference ranges; other pituitary hormone abnormalities may be present

• If the diagnosis of ovarian failure is confirmed in patients younger than 30 years, a karyotype evaluation should be performed to exclude Turner syndrome or the presence of Y chromatin material because of the high risk of gonadal tumors, mandating gonadectomy

• In the presence of a normal karyotype, autoimmune disease is likely (30% of these patients); therefore, assessment for autoimmune disorders, including thyroid or adrenal disease, is important; testing may include TSH, antithyroid antibodies, morning serum cortisol, and ACTH evaluations, followed by an ACTH stimulation test if necessary

In men or women with low FSH, high prolactin, or high FSH levels (the latter being suggestive of gonadotroph adenoma in the appropriate clinical setting), a magnetic resonance imaging (MRI) scan of the pituitary gland must be obtained.

In women with clinical features and laboratory findings suggestive of an ovarian tumor but with negative results from imaging studies, laparoscopy may be performed to help locate ovarian masses.

Management

Medical treatment in patients with abnormal levels of FSH depends on the underlying etiology. In women with primary (ovarian) or secondary (pituitary) hypogonadism, hormone replacement therapy may be administered (estrogen and progesterone). However, a study by the Women's Health Initiative showed health risks from using estrogens plus progesterone. [3]

In men with primary (testes) or secondary (pituitary) hypogonadism, testosterone replacement therapy is administered, either intramuscularly or with patches or gel.

Surgery is the treatment of choice for patients with gonadotroph adenomas, adrenal tumors, or gonadal tumors, unless contraindicated for other medical reasons.

Next:

Pathophysiology

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.

    View Media Gallery

  • 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.

    View Media Gallery

  • Idiopathic hypogonadotropic hypogonadism associated with mental retardation: 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.

    View Media Gallery

  • 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.

    What happens if FSH is high in males?

    If you are a man, high FSH levels may mean: Your testicles have been damaged due to chemotherapy, radiation, infection, or alcohol abuse. You have Klinefelter syndrome, a genetic disorder affects sexual development in males. It often causes infertility.

    What is the best treatment for high FSH level?

    Using donor eggs for IVF is an extremely effective treatment for patients with high FSH levels, and it is much more common that you think. Babies conceived with donor eggs have brought untold joy to so many families who would otherwise never have been able to get pregnant.

    Can FSH levels be lowered in males?

    Thus increased FSH levels in men with idiopathic oligospermia can be selectively reduced by pulsatile LHRH treatment.

    Can you still produce sperm with high FSH?

    Elevated FSH Levels and male infertility When the brain senses that the testicles are making less sperm than normal, it releases more FSH into the bloodstream to get the testicles to make more sperm. An elevated FSH therefore suggests that the sperm-producing capacity of the testicles is decreased.