Physiology, Follicle Stimulating Hormone

Issues of Concern

• Fertility
• Sexual development
• Amenorrhea
• Menopause
• Pituitary adenomas

Cellular Level

FSH is a glycoprotein dimer with alpha and beta subunits. The beta subunit is unique to FSH, while the alpha subunit is the same as in TSH, hCG, and LH. [2] 

GnRH stimulates FSH release. The hypothalamus produces GnRH, and it is released into the hypophyseal portal circulation to act on G-protein-coupled receptors at gonadotropic cells of the anterior pituitary. Those gonadotropic cells produce FSH and luteinizing hormone (LH) and release them into the peripheral circulation.

GnRH release occurs in a pulsatile manner, with low pulse frequencies stimulating more FSH production and high pulse frequencies stimulating more LH production.[1] Continuous use of GnRH suppresses the release of FSH and LH from the anterior pituitary which inhibits ovulation and estrogen production in women. Clinically, GnRH agonists like leuprolide work via this mechanism.[3]

In women, negative feedback from estrogen levels inhibits FSH secretion.[4] In men, levels of inhibin B, secreted by the Sertoli cells in response to FSH, inhibit FSH secretion via negative feedback.[5]

Development

During fetal development, GnRH producing neurons develop from the epithelium of the medial olfactory pit and then migrate to the hypothalamus.[6] The anterior pituitary gland develops from Rathke’s pouch, a portion of the oral cavity.[2] 

In the second and third trimesters of pregnancy, as well during the first 3 to 6 months of infancy, the pituitary gland secretes LH and FSH.[7] LH and FSH levels peak mid-pregnancy as the first ovarian follicle or seminiferous tubule mature.[6] 

• In males, FSH stimulates Sertoli cell proliferation, which is the most significant contributor to testicular volume in children.[7] The Sertoli cells produce an anti-mullerian hormone (AMH), which causes the involution of the Mullerian ducts, preventing the formation of female internal genitalia.[6]

Clinical correlation of the early infancy LH and FSH surge:

• The lack of the normal infancy peak of LH and FSH might identify and diagnose infants, especially males, who have hypogonadotropic hypogonadism.  
• Girls with monosomy Turner syndrome (45, XO) have an elevation of FSH up to 6 years old due to lack of negative feedback from nonfunctional ovaries, while girls with mosaicism (45, X/46, XX) have a much lower FSH elevation due to partial ovarian function.[6]

During puberty, the hypothalamus secretes GnRH in a pulsatile manner, which stimulates the anterior pituitary to increase secretion of LH and FSH.[6]

Organ Systems Involved

Hypothalamic-Pituitary-Gonadal Axis

The hypothalamus secretes GnRH, which stimulates the anterior pituitary to release FSH and LH. In females, FSH receptors are located in the granulosa cells of the ovaries. In males, FSH receptors are found in the Sertoli cells of the testes.[2]

Function

Females

• Estrogen production
• Follicular development

Males

• Induction and maintenance of spermatogenesis

Mechanism

Females

Estrogen Production

FSH stimulates granulosa cells in the ovarian follicles to synthesize aromatase, which converts androgens produced by the thecal cells to estradiol.

Follicular Development and the Menstrual Cycle

During the follicular phase of the menstrual cycle, FSH stimulates the maturation of ovarian follicles. As a dominant follicle takes over and secretes estradiol and inhibin, FSH secretion is suppressed. When the dominant follicle produces enough estradiol to maintain levels of 200 to 300 pg/ml for 48 hours, the hypothalamus responds with a surge of GnRH which stimulates the secretion of gonadotropic hormones instead inhibiting them. FSH peaks at the same time as the LH surge that causes ovulation. FSH then remains low throughout the luteal phase, preventing the development of new follicles.[2]

Males

FSH, along with testosterone, is necessary for maintaining normal sperm count and function. Studies have shown that FSH deprivation not only lowers sperm count but also affects the quality of the remaining sperm. [8]

Pathophysiology

Elevated levels of FSH are associated with unresponsive gonads or hyperfunctioning pituitary adenomas. Low levels of FSH are associated with either hypothalamic or anterior pituitary dysfunction.

Clinical Significance

FSH Levels and Male Infertility

If males present with small, firm testes and azoospermia or oligospermia, elevated FSH levels can be used to differentiate Klinefelter syndrome from hypothalamic or pituitary insufficiency.  If testicular size is normal and patients present with azoospermia or oligospermia, FSH levels can be used to determine whether the cause is a primary impairment of spermatogenesis or obstructive. In an obstructive cause of infertility, FSH levels remain normal, while a primary impairment of spermatogenesis will present with elevated FSH levels.

Several FSH preparations have been used to treat secondary hypogonadism in males. These preparations have been reasonably successful at inducing spermatogenesis and achieving paternity. [8]

Polycystic Ovarian Syndrome

Polycystic ovarian syndrome (PCOS) is a syndrome characterized by elevated androgens, polycystic ovaries, and anovulation.  Patients with PCOS often present with hirsutism, obesity, insulin resistance, menstrual irregularity, and infertility.[9]

In PCOS, the LH:FSH ratio is skewed due to persistently rapid GnRH pulses. These GnRH pulses lead to an increased LH: FSH ratio. This skewed ratio leads to the theca cells of the ovaries producing excess androgen while the granulosa cells do not produce enough aromatase to convert the androgens to estradiol.[1]

Hypogonadotropic Hypogonadism

In cases of amenorrhea with low levels of FSH and LH, the fault lies with either the hypothalamus or the pituitary gland.

Stress-Induced Hypogonadotropic Hypogonadism

When calorie intake falls short of energy expenditure, the physiological stress decreases hypothalamic GnRH pulse frequency and amplitude, leading to low FSH and LH levels. This explains the anovulation and amenorrhea that can occur in female athletes and individuals with eating disorders due to lack of adequate caloric intake or excessive exercise.[2][1]

Kallman Syndrome

During fetal development, GnRH producing neurons of the hypothalamus develop from the epithelium of the medial olfactory pit and then migrate to their proper place.[6] In Kallmann syndrome, a defect in this migratory process leads to the combination of anosmia and hypogonadotropic hypogonadism.[2]

Primary Ovarian Insufficiency

In cases of amenorrhea with elevated levels of FSH, the problem lies in the ovaries.

Premature ovarian failure occurs when ovarian failure and menopause occur before age 40. When this happens, FSH levels are elevated due to the lack of negative feedback from the ovaries. Although there may be multiple genetic causes, most cases are idiopathic.

Turner Syndrome is the most common genetic disorder causing premature ovarian failure. Turner Syndrome is caused by the loss of an X chromosome (XO karyotype). Girls with Turner syndrome will present with primary amenorrhea and underdeveloped ovaries (streak ovaries) and elevated FSH levels.[10]

Pituitary Adenomas

Pituitary adenomas can develop from any of the cell types in the pituitary.  Pituitary adenomas derived from gonadotropic cells are most often nonfunctioning or function within normal hormone levels and are diagnosed due to symptoms from mass effect rather than hormone secretions. However, in sporadic, these tumors can secrete excess FSH and/or LH and can cause ovarian hyperstimulation.[11] 

Medications

GnRH Agonists and Antagonists

GnRH agonists initially stimulate secretion of LH and FSH, but when given continuously, suppress LH and FSH release. This results in ovarian suppression and decreased estrogen levels. GnRH antagonists can acutely suppress LH and FSH secretion.[2]  

Both GnRH agonists and antagonists have a role in the treatment of certain breast and prostate cancers, endometriosis, and uterine leiomyomas.

Assisted Reproduction Techniques (ART)

Techniques such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) help couples by using FSH to stimulate multiple follicles in the ovaries to harvest multiple eggs for fertilization. FSH is available ias urinary FSH with or without LH or recombinant FSH.[12] GnRH agonists or antagonists can be used during these cycles to prevent the LH surge and ovulation.[2]