Follicle-stimulating hormone (fsh) and luteinizing hormone (lh) are secreted by the _____.

The menstrual cycle is a rhythmic sequence of events reflecting communication between the brain, ovary and uterus.

This is called the hypothalamic-pituitary-ovarian (HPO) axis. Hormones produced in the hypothalamus and pituitary gland (brain) and follicles (ovary) coordinate the cycle events. 

Understanding the menstrual cycle unlocks a better understanding of why your doctor gives you certain medications to promote fertility. Disorders of the menstrual cycle can also contribute to infertility. 

Ovulation

On average, a menstrual cycle is 28 days long, but can range from 25-35 days. The cycle length is measured from the first day of bleeding in one cycle (CD1, cycle day 1) to the first day of bleeding in a subsequent cycle. There are two main phases of the menstrual cycle, the follicular phase and the luteal phase. Ovulation occurs approximately 14 days before the onset of the next menstrual period. For example, in a 28 day cycle, ovulation typically occurs around day 14; in a 26 day cycle it occurs around day 12, and in a 30 day cycle it occurs around day 16. Ovulation demarcates the transition from the follicular phase to the luteal phase.

Menstrual cycle: Two main phases

Introduction

Follicle-stimulating hormone (FSH) is a hormone produced by the anterior pituitary in response to gonadotropin-releasing hormone (GnRH) from the hypothalamus.[1] 

FSH plays a role in sexual development and reproduction in both males and females.

Issues of Concern

• Fertility

• Sexual development

• Amenorrhea

• Menopause

• Pituitary adenomas

Cellular

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]

Review Questions

References

Stamatiades GA, Kaiser UB. Gonadotropin regulation by pulsatile GnRH: Signaling and gene expression. Mol Cell Endocrinol. 2018 Mar 05;463:131-141. [PMC free article: PMC5812824] [PubMed: 29102564]

Barbieri RL. The endocrinology of the menstrual cycle. Methods Mol Biol. 2014;1154:145-69. [PubMed: 24782009]

Yonkers KA, Simoni MK. Premenstrual disorders. Am J Obstet Gynecol. 2018 Jan;218(1):68-74. [PubMed: 28571724]

Shaw ND, Histed SN, Srouji SS, Yang J, Lee H, Hall JE. Estrogen negative feedback on gonadotropin secretion: evidence for a direct pituitary effect in women. J Clin Endocrinol Metab. 2010 Apr;95(4):1955-61. [PMC free article: PMC2853991] [PubMed: 20133465]

Boepple PA, Hayes FJ, Dwyer AA, Raivio T, Lee H, Crowley WF, Pitteloud N. Relative roles of inhibin B and sex steroids in the negative feedback regulation of follicle-stimulating hormone in men across the full spectrum of seminiferous epithelium function. J Clin Endocrinol Metab. 2008 May;93(5):1809-14. [PMC free article: PMC2386680] [PubMed: 18270253]

Lanciotti L, Cofini M, Leonardi A, Penta L, Esposito S. Up-To-Date Review About Minipuberty and Overview on Hypothalamic-Pituitary-Gonadal Axis Activation in Fetal and Neonatal Life. Front Endocrinol (Lausanne). 2018;9:410. [PMC free article: PMC6070773] [PubMed: 30093882]

Grinspon RP, Urrutia M, Rey RA. Male Central Hypogonadism in Paediatrics - the Relevance of Follicle-stimulating Hormone and Sertoli Cell Markers. Eur Endocrinol. 2018 Sep;14(2):67-71. [PMC free article: PMC6182919] [PubMed: 30349597]

Nieschlag E, Simoni M, Gromoll J, Weinbauer GF. Role of FSH in the regulation of spermatogenesis: clinical aspects. Clin Endocrinol (Oxf). 1999 Aug;51(2):139-46. [PubMed: 10468980]

Krishnan A, Muthusami S. Hormonal alterations in PCOS and its influence on bone metabolism. J Endocrinol. 2017 Feb;232(2):R99-R113. [PubMed: 27895088]

Pouresmaeili F, Fazeli Z. Premature ovarian failure: a critical condition in the reproductive potential with various genetic causes. Int J Fertil Steril. 2014 Apr;8(1):1-12. [PMC free article: PMC3973172] [PubMed: 24696764]

Kihara M, Sugita T, Nagai Y, Saeki N, Tatsuno I, Seki K. Ovarian hyperstimulation caused by gonadotroph cell adenoma: a case report and review of the literature. Gynecol Endocrinol. 2006 Feb;22(2):110-3. [PubMed: 16603438]

Pouwer AW, Farquhar C, Kremer JA. Long-acting FSH versus daily FSH for women undergoing assisted reproduction. Cochrane Database Syst Rev. 2015 Jul 14;(7):CD009577. [PubMed: 26171903]

What secretes FSH follicle stimulating hormone and LH luteinizing hormone?

Where is the follicle stimulating hormone secreted from?

Which hormone causes FSH and LH to be released quizlet?