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:
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LH and testosterone levels
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Prolactin levels
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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
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sem*n 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:
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LH and testosterone levels
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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
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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:
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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
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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
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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.
