Follicle-Stimulating Hormone Abnormalities

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Practice Essentials

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.

Diagnosis

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

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:

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 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.[2]

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.

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:

Causes of high FSH level

Primary hypogonadism: This can be congenital or acquired

Epidemiology

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.

Mortality/Morbidity

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

History

The symptomatology depends on the disease causing the low or high follicle-stimulating hormone (FSH) levels and varies between men and women.

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 presenting with low FSH levels or high FSH levels secondary to ovarian failure, manifestations include oligomenorrhea or amenorrhea.

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[17] and a thickened endometrium; this leads to disturbed menstrual cycles, ie, oligomenorrhea or amenorrhea.

Physical

The physical examination findings also depend on the disease that underlies the abnormal follicle-stimulating hormone level. The following important points must be remembered.

In men presenting with hypogonadism, findings depend on the timing of onset during life and on the duration of testosterone deficiency.

In women presenting with hypogonadism (oligomenorrhea or amenorrhea), physical examination findings may include hirsutism and/or masculinization (eg, frontal balding, clitoromegaly, increased muscle mass) only if an excess of androgens is present, which is not frequent. The examination may reveal stigmata of Turner syndrome (eg, short stature, webbed neck, shield chest, wide carrying angle of the arms), short fourth metacarpals, cardiovascular anomalies (coarctation of aorta, bicuspid aortic valve), or evidence for other endocrine deficiencies or autoimmune diseases (eg, Addison disease, vitiligo, Hashimoto thyroiditis).

In men and women with pituitary macroadenomas, visual-field examination findings may be abnormal. Other signs of hypopituitarism may also be detected upon examination.

Causes

See Pathophysiology.

Laboratory Studies

Perform additional laboratory studies in men presenting with low follicle-stimulating hormone (FSH) levels.

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:

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:

Imaging Studies

In men or women with low follicle-stimulating hormone (FSH), high prolactin, or high FSH levels (the latter being suggestive of gonadotroph adenoma in the appropriate clinical setting), an MRI scan of the pituitary gland must be obtained.

In women with very high DHEAS levels (>700 mcg/dL), perform CT scanning of the adrenals to exclude an androgen-secreting tumor.

In women with very high testosterone levels (>200 ng/mL), perform imaging studies of the ovaries (CT scan, ultrasound).

In men with high estradiol levels, imaging of the testes (ultrasound) should be performed and, subsequently, the adrenals (CT scan) if the testicular ultrasound findings are normal.

Procedures

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, which could be small and are frequently difficult to detect using routine imaging.

Medical Care

Medical treatment in patients with abnormal levels of follicle-stimulating hormone (FSH) depends on the underlying etiology. Appropriate articles are available that contain detailed discussions. However, the following points deserve mention:

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 in 16,608 postmenopausal women over 5.2 years of follow-up. Excess risks attributable to estrogens plus progesterone included more cardiovascular events, strokes, pulmonary emboli, and invasive breast cancers, but less risk of colorectal cancer. Hormone replacement therapy should take into account all of these factors. Also, other pituitary deficiencies (eg, thyroid, adrenal) must be corrected in the appropriate setting.[2]

In men with primary (testes) or secondary (pituitary) hypogonadism, testosterone replacement therapy is administered, either intramuscularly or with patches or gel. Again, other pituitary deficiencies must be corrected.

In men and women, treatment targeted at the underlying etiology may suffice. In patients with prolactinomas, medical treatment with a dopamine agonist lowers prolactin levels and may normalize FSH, LH, and testosterone/estradiol levels.[18]  In patients with hemochromatosis, repeated phlebotomy to remove iron may reverse the gonadotropin deficiency.

A report on the use of recombinant human FSH (rhFSH) in the treatment of male infertility found that the total mobile sperm count (TMSC) rose in men with isolated FSH deficiency who received rhFSH therapy.[19] The investigators studied 61 infertile men, including 13 patients with isolated FSH deficiency, who received 100-150 IU of rhFSH 2-3 times per week. The TMSC rose from 6.64 (±3.27) million to 32.4 (±9.09) million in the isolated FSH deficiency patients.

A study by Bry-Gauillard et al of women with isolated hypogonadotropic hypogonadism in association with Kallmann syndrome found that a significant rise in serum estradiol and inhibin B concentrations, as well as an increase in the number of larger antral follicles, occurred via ovarian stimulation with rhFSH. While a rise was also seen in the anti-Müllerian hormone level and smaller antral follicle count with rhFSH administration, these values subsequently fell even with continued stimulation.[20]

A study by Zhang et al indicated that in patients with idiopathic hypogonadotropic hypogonadism, the use of sequential urinary FSH (uFSH)/human chorionic gonadotropin (hCG) injections is as effective as the administration of continual uFSH/hCG injections in inducing spermatogenesis and masculinization.[21]

Hormone replacement therapy

Hormone replacement therapy must be monitored carefully. Women on estrogen therapy who have an intact uterus should receive progesterone therapy to prevent endometrial hyperplasia, and they should have yearly breast examinations and mammograms as indicated.

Patients should have yearly Papanicolaou tests (Pap smears).

If vaginal bleeding occurs while on therapy, an endometrial biopsy and/or dilation and curettage should be considered to determine the presence of endometrial cancer.

Men on testosterone replacement therapy should have yearly prostate-specific antigen tests and regular rectal examinations to monitor for prostate carcinoma.

A study by Rohayem et al indicated that in adult males, the efficacy of gonadotropin replacement for hypogonadotropic hypogonadism is predicted by the cause of the condition. The study found, for example, that men with Kallmann syndrome had the worst responses, while responses in males with congenital/infancy-acquired multiple pituitary hormone deficiency was also poor. However, men with postpubertally acquired multiple pituitary hormone deficiency had among the best outcomes.[22]

Surgical Care

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

Consultations

Consultation with an endocrinologist or gynecologist is frequently helpful for appropriate diagnostic evaluation and management.

Medication Summary

The goals of pharmacotherapy are to correct hormonal imbalances, to prevent complications, and to reduce morbidity.

Conjugated estrogens (Premarin)

Clinical Context:  Restore estrogen levels to concentrations that induce negative feedback at gonadotrophic regulatory centers, which, in turn, reduces FSH release from the pituitary gland. Vaginal estrogen creams may alleviate vaginal dryness and urogenital symptoms, but systemic absorption is not usually sufficient to provide systemic effect.

Estradiol (Climara Transdermal, Estrace, Estraderm Transdermal, Gynodiol)

Clinical Context:  Restores estrogen levels to concentrations that induce negative feedback at gonadotrophic regulatory centers, which, in turn, reduces FSH release from pituitary. Vaginal estrogen creams may alleviate vaginal dryness and urogenital symptoms, but systemic absorption is not usually sufficient to provide systemic effect.

Medroxyprogesterone (Cycrin, Provera)

Clinical Context:  Progestins stop endometrial cell proliferation, allowing organized sloughing of cells after withdrawal; typically does not stop acute bleeding episode but produces a normal bleeding episode following withdrawal.

Testosterone (Delatestryl injection, AndroGel, Androderm, Testoderm TTS)

Clinical Context:  Promotes the growth and development of the male sex organs and maintains secondary sex characteristics in androgen-deficient males

Class Summary

Estrogen is used to induce negative feedback at gonadotrophic regulatory centers, which, in turn, reduces release of gonadotropins. Progestins are used to prevent endometrial hyperplasia in patients with an intact uterus. Testosterone is used in males to restore sexual function and to replace the benefits of endogenous testosterone.

What are follicle-stimulating hormones (FSH)?What are the functions of follicle-stimulating hormones (FSH) and luteinizing hormones (LH) in the male reproductive system?What are the functions of follicle-stimulating hormones (FSH) and luteinizing hormones (LH) in the female reproductive system?What causes follicle-stimulating hormones (FSH) and luteinizing hormones (LH) to fail?Which lab studies are performed in the evaluation low follicle-stimulating hormone (FSH) levels in men?Which lab studies are performed in the evaluation high follicle-stimulating hormone (FSH) levels in men?Which lab studies are performed in the evaluation low follicle-stimulating hormone (FSH) levels in women?Which lab studies are performed in the evaluation high follicle-stimulating hormone (FSH) levels in women?What is the role of MRI in the evaluation of follicle-stimulating hormone (FSH) level abnormalities?What is the role of laparoscopy in the evaluation of follicle-stimulating hormone (FSH) level abnormalities in women?What is the treatment options for women with follicle-stimulating hormones (FSH) abnormalities?What is the treatment options for men with follicle-stimulating hormones (FSH) abnormalities?What is the role of surgery in the treatment of follicle-stimulating hormone (FSH) abnormalities?How are the abnormalities of follicle-stimulating hormone (FSH) grouped?What are the congenital causes of low follicle-stimulating hormone (FSH) levels?What are the acquired causes of low follicle-stimulating hormone (FSH) levels?What are the congenital causes of high follicle-stimulating hormone (FSH) levels?What are the acquired causes of high follicle-stimulating hormone (FSH) levels?What is the prevalence of follicle-stimulating hormone (FSH) abnormalities?What are the mortality rate and morbidity for follicle-stimulating hormone (FSH) abnormalities?What are the signs and symptoms of follicle-stimulating hormone (FSH) abnormalities?Which history findings suggest low follicle-stimulating hormone (FSH) abnormalities in men?Which history findings suggest high follicle-stimulating hormone (FSH) abnormalities in men?Which history findings suggest low follicle-stimulating hormone (FSH) abnormalities in women?Which history findings suggest high follicle-stimulating hormone (FSH) abnormalities in women?What will determine the physical findings of follicle-stimulating hormone (FSH) abnormality?What are the physical findings suggestive of low follicle-stimulating hormone (FSH) levels in males in utero?What are the physical findings suggestive of low follicle-stimulating hormone (FSH) levels in males prior to puberty?What are the physical findings suggestive of low follicle-stimulating hormone (FSH) levels in males after puberty?What are physical findings suggestive of low follicle-stimulating hormone (FSH) levels in women?What are physical findings of macroadenoma in patients with abnormal follicle-stimulating hormone (FSH) levels?Which lab studies should be performed in men with low follicle-stimulating hormone (FSH) levels?Which lab studies should be performed in men with high follicle-stimulating hormone (FSH) levels?Which lab studies should be performed in women with low follicle-stimulating hormone (FSH) levels?Which lab studies should be performed in women with high follicle-stimulating hormone (FSH) levels?What is the role of imaging studies is the evaluation of abnormal follicle-stimulating hormone (FSH) levels?When is laparoscopy indicated in women with abnormal follicle-stimulating hormone (FSH) levels?How is medical treatment selected for follicle-stimulating hormone (FSH) abnormalities?What are the medical treatment options for women with abnormal levels of follicle-stimulating hormone (FSH)?What are the medical treatment options for men with abnormal levels of follicle-stimulating hormone (FSH)?What treatment options for the underlying etiologies of follicle-stimulating hormone (FSH) abnormalities in both men and women?What is the role of hormone replacement therapy (HRT) in the treatment of follicle-stimulating hormone (FSH) abnormalities?What is the efficacy of hormone replacement therapy (HRT) for the treatment of follicle-stimulating hormone (FSH) abnormalities?When is surgery indicated for the treatment of follicle-stimulating hormone (FSH) abnormalities?Which specialist consultations are helpful in the management of follicle-stimulating hormone (FSH) abnormalities?What is the goal of drug treatment for follicle-stimulating hormone (FSH) abnormalities?Which medications in the drug class Hormone replacement agents are used in the treatment of Follicle-Stimulating Hormone Abnormalities?

Author

Serge A Jabbour, MD, FACP, FACE, Professor of Medicine, Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Romesh Khardori, MD, PhD, FACP, Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

References

  1. Grover A, Smith CE, Gregory M, et al. Effects of FSH receptor deletion on epididymal tubules and sperm morphology, numbers, and motility. Mol Reprod Dev. 2005 Oct. 72(2):135-44. [View Abstract]
  2. Walvoord E. Sex steroid replacement for induction of puberty in multiple pituitary hormone deficiency. Pediatr Endocrinol Rev. 2009 Jan. 6 Suppl 2:298-305. [View Abstract]
  3. Topaloglu AK. Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism. J Clin Res Pediatr Endocrinol. 2017 Dec 30. 9 (Suppl 2):113-22. [View Abstract]
  4. Karges B, de Roux N. Molecular genetics of isolated hypogonadotropic hypogonadism and Kallmann syndrome. Endocr Dev. 2005. 8:67-80. [View Abstract]
  5. Fraietta R, Zylberstejn DS, Esteves SC. Hypogonadotropic hypogonadism revisited. Clinics (Sao Paulo). 2013. 68 Suppl 1:81-8. [View Abstract]
  6. Zhang C, Verma V, Lyden ER, et al. The Role of Definitive Radiotherapy in Craniopharyngioma: A SEER Analysis. Am J Clin Oncol. 2017 Mar 3. [View Abstract]
  7. Otto AP, Franca MM, Correa FA, et al. Frequent development of combined pituitary hormone deficiency in patients initially diagnosed as isolated growth hormone deficiency: a long term follow-up of patients from a single center. Pituitary. 2015 Aug. 18(4):561-7. [View Abstract]
  8. Nagorny P, Sane N, Fasching B, Aussedat B, Danishefsky SJ. Probing the Frontiers of Glycoprotein Synthesis: The Fully Elaborated ß-Subunit of the Human Follicle-Stimulating Hormone. Angew Chem Int Ed Engl. 2011 Dec 9. [View Abstract]
  9. Dandona P, Dhindsa S, Chaudhuri A, et al. Hypogonadotrophic hypogonadism in type 2 diabetes. Aging Male. 2008 Sep. 11(3):107-17. [View Abstract]
  10. Ferhi K, Avakian R, Griveau JF, et al. Age as only predictive factor for successful sperm recovery in patients with Klinefelter's syndrome. Andrologia. 2009 Apr. 41(2):84-7. [View Abstract]
  11. Wikstrom AM, Dunkel L. Testicular function in Klinefelter syndrome. Horm Res. 2008. 69(6):317-26. [View Abstract]
  12. Van Saen D, Gies I, De Schepper J, Tournaye H, Goossens E. Can pubertal boys with Klinefelter syndrome benefit from spermatogonial stem cell banking?. Hum Reprod. 2011 Dec 12. [View Abstract]
  13. Desai SS, Roy BS, Mahale SD. Mutations and polymorphisms in FSH receptor: functional implications in human reproduction. Reproduction. 2013 Dec. 146(6):R235-48. [View Abstract]
  14. Rohayem J, Luberto A, Nieschlag E, Zitzmann M, Kliesch S. Delayed treatment of undescended testes may promote hypogonadism and infertility. Endocrine. 2017 Mar. 55 (3):914-24. [View Abstract]
  15. Cools M, Rooman RP, Wauters J, et al. A nonmosaic 45,X karyotype in a mother with Turner's syndrome and in her daughter. Fertil Steril. 2004 Oct. 82(4):923-5. [View Abstract]
  16. Livadas S, Xekouki P, Kafiri G, et al. Spontaneous pregnancy and birth of a normal female from a woman with Turner syndrome and elevated gonadotropins. Fertil Steril. 2005 Mar. 83(3):769-72. [View Abstract]
  17. Ardawi MS, Rouzi AA. Plasma adiponectin and insulin resistance in women with polycystic ovary syndrome. Fertil Steril. 2005 Jun. 83(6):1708-16. [View Abstract]
  18. Trabado S, Maione L, Salenave S, Baron S, Galland F, Bry-Gauillard H, et al. Estradiol levels in men with congenital hypogonadotropic hypogonadism and the effects of different modalities of hormonal treatment. Fertil Steril. 2011 Jun. 95(7):2324-9, 2329.e1-3. [View Abstract]
  19. Efesoy O, Cayan S, Akbay E. The efficacy of recombinant human follicle-stimulating hormone in the treatment of various types of male factor infertility at a single university hospital. J Androl. 2009 May 28. [View Abstract]
  20. Bry-Gauillard H, Larrat-Ledoux F, Levaillant JM, et al. Anti-Mullerian Hormone and Ovarian Morphology in Women With Isolated Hypogonadotropic Hypogonadism/Kallmann Syndrome: Effects of Recombinant Human FSH. J Clin Endocrinol Metab. 2017 Apr 1. 102 (4):1102-11. [View Abstract]
  21. Zhang M, Tong G, Liu Y, et al. Sequential Versus Continual Purified Urinary FSH/hCG in Men With Idiopathic Hypogonadotropic Hypogonadism. J Clin Endocrinol Metab. 2015 Jun. 100(6):2449-55. [View Abstract]
  22. Rohayem J, Sinthofen N, Nieschlag E, Kliesch S, Zitzmann M. Causes of hypogonadotropic hypogonadism predict response to gonadotropin substitution in adults. Andrology. 2016 Jan. 4 (1):87-94. [View Abstract]

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

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.

Magnetic resonance imaging (MRI) scan of pituitary macroadenoma.

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

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

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

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.

Magnetic resonance imaging (MRI) scan of pituitary macroadenoma.

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

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