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The [[hypothalamus]] is located in the brain and secretes GnRH.<ref name="pmid15082521">{{cite journal | author = Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR | title = Gonadotropin-releasing hormone receptors | journal = Endocr. Rev. | volume = 25 | issue = 2 | pages = 235–75 |date=April 2004 | pmid = 15082521 | doi = 10.1210/er.2003-0002| url = | issn = }}</ref> GnRH travels down the anterior portion of the pituitary via the [[hypophyseal portal system]] and binds to receptors on the secretory cells of the [[adenohypophysis]].<ref name="pmid18601683">{{cite journal | author = Charlton H | title = Hypothalamic control of anterior pituitary function: a history | journal = J. Neuroendocrinol. | volume = 20 | issue = 6 | pages = 641–6 |date=June 2008 | pmid = 18601683 | doi = 10.1111/j.1365-2826.2008.01718.x | url = | issn = }}</ref> In response to GnRH stimulation these cells produce LH and FSH, which travel into the blood stream.<ref name="pmid15723162">{{cite journal | author = Vadakkadath Meethal S, Atwood CS | title = The role of hypothalamic-pituitary-gonadal hormones in the normal structure and functioning of the brain | journal = Cell. Mol. Life Sci. | volume = 62 | issue = 3 | pages = 257–70 |date=February 2005 | pmid = 15723162 | doi = 10.1007/s00018-004-4381-3 | url = | issn = }}</ref>
The [[hypothalamus]] is located in the brain and secretes GnRH.<ref name="pmid15082521">{{cite journal | author = Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR | title = Gonadotropin-releasing hormone receptors | journal = Endocr. Rev. | volume = 25 | issue = 2 | pages = 235–75 |date=April 2004 | pmid = 15082521 | doi = 10.1210/er.2003-0002| url = | issn = }}</ref> GnRH travels down the anterior portion of the pituitary via the [[hypophyseal portal system]] and binds to receptors on the secretory cells of the [[adenohypophysis]].<ref name="pmid18601683">{{cite journal | author = Charlton H | title = Hypothalamic control of anterior pituitary function: a history | journal = J. Neuroendocrinol. | volume = 20 | issue = 6 | pages = 641–6 |date=June 2008 | pmid = 18601683 | doi = 10.1111/j.1365-2826.2008.01718.x | url = | issn = }}</ref> In response to GnRH stimulation these cells produce LH and FSH, which travel into the blood stream.<ref name="pmid15723162">{{cite journal | author = Vadakkadath Meethal S, Atwood CS | title = The role of hypothalamic-pituitary-gonadal hormones in the normal structure and functioning of the brain | journal = Cell. Mol. Life Sci. | volume = 62 | issue = 3 | pages = 257–70 |date=February 2005 | pmid = 15723162 | doi = 10.1007/s00018-004-4381-3 | url = | issn = }}</ref>


These two hormones play an important role in communicating to the gonads. In females FSH and LH act primarily to activate the [[ovaries]] to produce estrogen and inhibin and to regulate the [[menstrual cycle]] and [[ovarian cycle]]. Estrogen forms a [[negative feedback loop]] by inhibiting the production of GnRH in the hypothalamus. [[Inhibin]] acts to inhibit [[activin]], which is a peripherally produced hormone that positively stimulates GnRH-producing cells. [[Follistatin]], which is also produced in all body tissue, inhibits activin and gives the rest of the body more control over the axis. In males LH stimulates the interstitial cells located in the [[testes]] to produce testosterone, and FSH plays a role in [[spermatogenesis]]. Only small amounts of estrogen are secreted in males. Recent research has shown that a neurosteroid axis exists, which helps the cortex to regulate the hypothalamus’s production of GnRH.<ref name="pmid19493163">{{cite journal | author = Meethal SV, Liu T, Chan HW, Ginsburg E, Wilson AC, Gray DN, Bowen RL, Vonderhaar BK, Atwood CS | title = Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors | journal = J. Neurochem. | volume = 110 | issue = 3 | pages = 1014–27 |date=August 2009 | pmid = 19493163 | pmc = 2789665 | doi = 10.1111/j.1471-4159.2009.06192.x | url = | issn = }}</ref> In addition, [[leptin]] and [[insulin]] have stimulatory effects and [[ghrelin]] has inhibitory effects on [[gonadotropin-releasing hormone]] (GnRH) secretion from the [[hypothalamus]].<ref>{{cite doi|10.1093/humupd/dmt033}}</ref> Other substances play a role in this important neuroendocrine negative feedback pathway. Studies have shown that kisspeptins, a group of amino-acid peptides, and their G-protein-coupled receptor (GPR54) have a critical function in the secretion of GnRH and the negative feedback of testosterone and estradiol on the hypothalamus. Administration of kisspeptin has been shown to increase GnRH secretion in neuronal cell lines. <ref>http://www.ncbi.nlm.nih.gov/pubmed/19576263</ref> Furthermore, although acute administration of kisspeptin seems to increase LH, FSH and testosterone secretion, chronic administration lowers serum LH levels in monkeys.<ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528850/</ref><ref>http://www.ncbi.nlm.nih.gov/pubmed/16469799</ref> Manipulation of the kisspeptin–GPR54 pathway represents another potential target for future male contraceptive therapy.<ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528850/</ref>
These two hormones play an important role in communicating to the gonads. In females FSH and LH act primarily to activate the [[ovaries]] to produce estrogen and inhibin and to regulate the [[menstrual cycle]] and [[ovarian cycle]]. Estrogen forms a [[negative feedback loop]] by inhibiting the production of GnRH in the hypothalamus. [[Inhibin]] acts to inhibit [[activin]], which is a peripherally produced hormone that positively stimulates GnRH-producing cells. [[Follistatin]], which is also produced in all body tissue, inhibits activin and gives the rest of the body more control over the axis.


LH stimulates the interstitial cells located in the [[testes]] to produce testosterone, and FSH plays a role in [[spermatogenesis]]. Only small amounts of estrogen are secreted in males. Recent research has shown that a neurosteroid axis exists, which helps the cortex to regulate the hypothalamus’s production of GnRH.<ref name="pmid19493163">{{cite journal | author = Meethal SV, Liu T, Chan HW, Ginsburg E, Wilson AC, Gray DN, Bowen RL, Vonderhaar BK, Atwood CS | title = Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors | journal = J. Neurochem. | volume = 110 | issue = 3 | pages = 1014–27 |date=August 2009 | pmid = 19493163 | pmc = 2789665 | doi = 10.1111/j.1471-4159.2009.06192.x | url = | issn = }}</ref> In addition, [[leptin]] and [[insulin]] have stimulatory effects and [[ghrelin]] has inhibitory effects on [[gonadotropin-releasing hormone]] (GnRH) secretion from the [[hypothalamus]].<ref>{{cite doi|10.1093/humupd/dmt033}}</ref> Other substances play a role in this important neuroendocrine negative feedback pathway. Studies have shown that kisspeptins, a group of amino-acid peptides, and their G-protein-coupled receptor (GPR54) have a critical function in the secretion of GnRH and the negative feedback of testosterone and estradiol on the hypothalamus. Administration of kisspeptin has been shown to increase GnRH secretion in neuronal cell lines. <ref>http://www.ncbi.nlm.nih.gov/pubmed/19576263</ref> Furthermore, although acute administration of kisspeptin seems to increase LH, FSH and testosterone secretion, chronic administration lowers serum LH levels in monkeys.<ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528850/</ref><ref>http://www.ncbi.nlm.nih.gov/pubmed/16469799</ref> Manipulation of the kisspeptin–GPR54 pathway represents another potential target for future male contraceptive therapy.<ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528850/</ref>
⚫
Receptors for hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function are expressed throughout the brain, and in particular the limbic system. The most researched of these hormones, the sex steroids, contain receptors throughout the brain, and several estrogenic, progestrogenic and androgenic effects have been reported in the brain related to the its development, maintenance and cognitive functions. Although less studied, receptors for gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and activins are also found throughout the limbic system on a number of cell types, and they also transduce signals from circulating hormones as demonstrated by their multiple effects on the growth, development, maintenance and function of the brain.

⚫
Receptors for hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function are expressed throughout the brain, and in particular the limbic system. The most researched of these hormones, the sex steroids, contain receptors throughout the brain, and several estrogenic, progestrogenic and androgenic effects have been reported in the brain related to the its development, maintenance and cognitive functions. Although less studied, receptors for gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and activins are also found throughout the limbic system on a number of cell types, and they also transduce signals from circulating hormones as demonstrated by their multiple effects on the growth, development, maintenance and function of the brain.

For the male gonadal axis, as described in chronological order: (1) the hypothalamus secretes GnRH; (2) GnRH travels down the anterior pituitary gland; (3) GnRH binds to receptors on the pituitary gland; (4) pituitary gland secretes LH and FSH due to the binding of GnRH to receptors; (5) LH and FSH travel in the blood stream to the testicles; (6) LH stimulates Leydig cells in the testicles to produce testosterone (required for spermatogenesis and other important biological processes); (7) FSH stimulates Sertoli cells to produce androgen binding globulin (ABG) and inhibin; (8) increasing levels of testosterone and inhibin cause a negative feedback on the pituitary and hypothalamus; (9) this decreases the production of LH and FSH; (10) in turn, this decreases the production of testosterone and inhibin.

For the female gonadal axis, as described in chronological order: (1) the hypothalamus secretes GnRH; (2) GnRH travels down the anterior pituitary gland; (3) GnRH binds to receptors on the pituitary gland; (4) pituitary gland secretes LH and FSH due to the binding of GnRH to receptors; (5) LH and FSH travel in the blood stream to the ovaries; (6) When LH and FSH bind to the ovaries they stimulate production of oestrogen and inhibin; (7) increasing levels of oestrogen and inhibin cause negative feedback on the pituitary and hypothalamus; (8) this leads to a decrease in the production of GnRH, LH and FSH; (9) in turn, this results in decreased production of oestrogen and Inhibin.


== Function ==
== Function ==

Revision as of 03:39, 23 February 2014

The hypothalamic–pituitary–gonadal axis (also called HPG axis or reproductive axis) refers to the collective interactions between and effects of three endocrine glands: the hypothalamus, pituitary gland, and gonads. Because the HPG axis often behaves in cooperation, physiologists and endocrinologists conveniently describe the HPG axis as a single integrated system. The hypothalamus produces gonadotropin-releasing hormone (GnRH). The anterior pituitary produces luteinizing hormones (LH) and follicle-stimulating hormones (FSH), and the gonads produce estrogen and testosterone.

Regulation of the reproductive axis starts at the hypothalamus, where neurosecretory cells synthesize and secrete gonadotropin-releasing hormones (GnRH) in a pulsatile fashion into the hypothalamic-hypophysial-portal circulation. The pulsatile release of GnRH from the arcuate nucleus of the hypothalamus regulates spermatogenesis by stimulating the gonadotrope cells of the anterior pituitary to episodically release follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which both regulate the gonadal function in both sexes.

The hypothalamic–pituitary–gonadal axis is a critical part in the development and regulation of a number of the body's systems, such as the reproductive and immune systems. This axis normally functions in a tightly regulated manner to produce concentrations of circulating steroids required for normal male sexual development, sexual function and fertility. Due to the feedback loops within the HPG axis, it is often challenging to ascribe structural and functional changes to a single HPG hormone during development, adulthood and senescence, for the reason that a change in the concentration of any hormone in the axis will modulate hormone concentrations and/or receptor expression patterns for all other members of the axis. An understanding of the reproductive axis is often essential for the assessment of abnormal development of the genitalia (e.g. pseudohermaphroditism), hypergonadism, hypogonadism, infertility and erectile dysfunction.

In oviparous female organisms (e.g. fish, reptiles, amphibians, birds), the HPG axis is commonly referred to as the hypothalamus-pituitary-gonadal-liver axis (HPGL-axis). Many egg-yolk and chorionic proteins are synthesized heterologously in the liver, which are necessary for oocyte growth and development. Examples of such necessary liver proteins are vitellogenin and choriogenin.

Location and Regulation mechanism

The hypothalamus is located in the brain and secretes GnRH.[1] GnRH travels down the anterior portion of the pituitary via the hypophyseal portal system and binds to receptors on the secretory cells of the adenohypophysis.[2] In response to GnRH stimulation these cells produce LH and FSH, which travel into the blood stream.[3]

These two hormones play an important role in communicating to the gonads. In females FSH and LH act primarily to activate the ovaries to produce estrogen and inhibin and to regulate the menstrual cycle and ovarian cycle. Estrogen forms a negative feedback loop by inhibiting the production of GnRH in the hypothalamus. Inhibin acts to inhibit activin, which is a peripherally produced hormone that positively stimulates GnRH-producing cells. Follistatin, which is also produced in all body tissue, inhibits activin and gives the rest of the body more control over the axis.

LH stimulates the interstitial cells located in the testes to produce testosterone, and FSH plays a role in spermatogenesis. Only small amounts of estrogen are secreted in males. Recent research has shown that a neurosteroid axis exists, which helps the cortex to regulate the hypothalamus’s production of GnRH.[4] In addition, leptin and insulin have stimulatory effects and ghrelin has inhibitory effects on gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus.[5] Other substances play a role in this important neuroendocrine negative feedback pathway. Studies have shown that kisspeptins, a group of amino-acid peptides, and their G-protein-coupled receptor (GPR54) have a critical function in the secretion of GnRH and the negative feedback of testosterone and estradiol on the hypothalamus. Administration of kisspeptin has been shown to increase GnRH secretion in neuronal cell lines. [6] Furthermore, although acute administration of kisspeptin seems to increase LH, FSH and testosterone secretion, chronic administration lowers serum LH levels in monkeys.[7][8] Manipulation of the kisspeptin–GPR54 pathway represents another potential target for future male contraceptive therapy.[9]

Receptors for hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function are expressed throughout the brain, and in particular the limbic system. The most researched of these hormones, the sex steroids, contain receptors throughout the brain, and several estrogenic, progestrogenic and androgenic effects have been reported in the brain related to the its development, maintenance and cognitive functions. Although less studied, receptors for gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) and activins are also found throughout the limbic system on a number of cell types, and they also transduce signals from circulating hormones as demonstrated by their multiple effects on the growth, development, maintenance and function of the brain.

For the male gonadal axis, as described in chronological order: (1) the hypothalamus secretes GnRH; (2) GnRH travels down the anterior pituitary gland; (3) GnRH binds to receptors on the pituitary gland; (4) pituitary gland secretes LH and FSH due to the binding of GnRH to receptors; (5) LH and FSH travel in the blood stream to the testicles; (6) LH stimulates Leydig cells in the testicles to produce testosterone (required for spermatogenesis and other important biological processes); (7) FSH stimulates Sertoli cells to produce androgen binding globulin (ABG) and inhibin; (8) increasing levels of testosterone and inhibin cause a negative feedback on the pituitary and hypothalamus; (9) this decreases the production of LH and FSH; (10) in turn, this decreases the production of testosterone and inhibin.

For the female gonadal axis, as described in chronological order: (1) the hypothalamus secretes GnRH; (2) GnRH travels down the anterior pituitary gland; (3) GnRH binds to receptors on the pituitary gland; (4) pituitary gland secretes LH and FSH due to the binding of GnRH to receptors; (5) LH and FSH travel in the blood stream to the ovaries; (6) When LH and FSH bind to the ovaries they stimulate production of oestrogen and inhibin; (7) increasing levels of oestrogen and inhibin cause negative feedback on the pituitary and hypothalamus; (8) this leads to a decrease in the production of GnRH, LH and FSH; (9) in turn, this results in decreased production of oestrogen and Inhibin.

Function

Reproduction

One of the most important functions of the HPG axis is to regulate reproduction by controlling the uterine and ovarian cycles.[10] In females, the positive feedback loop between estrogen and luteinizing hormone help to prepare the follicle in the ovary and the uterus for ovulation and implantation. When the egg is released, the ovary begins to produce progesterone to inhibit the hypothalamus and the anterior pituitary thus stopping the estrogen-LH positive feedback loop. If conception occurs, the fetus will take over the secretion of progesterone; therefore the mother cannot ovulate again. If conception does not occur, decreasing excretion of progesterone will allow the hypothalamus to restart secretion of GnRH. These hormone levels also control the uterine (menstrual) cycle causing the proliferation phase in preparation for ovulation, the secretory phase after ovulation, and menstruation when conception does not occur. The activation of the HPG axis in both males and females during puberty also causes individuals to acquire secondary sex characteristics.

In males, the production of GnRH, LH, and FSH are similar, but the effects of these hormones are different.[11] FSH stimulates sustentacular cells to release androgen-binding protein, which promotes testosterone binding. LH binds to the interstitial cells, causing them to secrete testosterone. Testosterone is required for normal spermatogenesis and inhibits the hypothalamus. Inhibin is produced by the spermatogenic cells, which, also through inactivating activin, inhibits the hypothalamus. After puberty these hormones levels remain relatively constant.

Life cycle

The activation and deactivation of the HPG axis also helps to regulate life cycles.[10] At birth FSH and LH levels are elevated, and females also have a lifetime supply of primary oocytes. These levels decrease and remain low through childhood. During puberty the HPG axis is activated by the secretions of estrogen from the ovaries or testosterone from the testes. This activation of estrogen and testosterone causes physiological and psychological changes. Once activated, the HPG axis continues to function in men for the rest of their life but becomes deregulated in women, leading to menopause. This deregulation is caused mainly by the lack of oocytes that normally produce estrogen to create the positive feedback loop. Over several years, the activity the HPG axis decreases and women are no longer fertile.[12]

Although males remain fertile until death, the activity of the HPG axis decreases. As males age, the testes begin to produce less testosterone, leading to a condition known as post-pubertal hypogonadism.[11] The cause of the decreased testosterone is unclear and a current topic of research. Post-pubertal hypogonadism results in progressive muscle mass decrease, increase in visceral fat mass, loss of libido, impotence, decreased attention, increased risk of fractures, and abnormal sperm production.

Sexual dimorphism and behavior

Sex steroids also affect behavior, because sex steroids affect our brain structure and functioning. During development, hormones help determine how neurons synapse and migrate to result in sexual dimorphisms.[13] These physical differences lead to differences in behavior. While GnRH has not been shown to have any direct influence on regulating brain structure and function, gonadotropins, sex steroids, and activin have been shown to have such effects. It is thought that FSH may have an important role in brain development and differentiation.

Testosterone levels have been shown to relate to aggression and sex drive. This helps create synaptogenesis by promoting neurite development and migration. Activin promotes neural plasticity throughout the lifespan and regulates the neurotransmitters of peripheral neurons. Environment can also affect hormones and behavior interaction.[14] Women have more connections between areas of language better enabling them to communicate than men. On average men out perform women on spatial reasoning tests, which is theorized to result from sexual differences. Testosterone has been linked to aggression and sex drive; therefore men tend to be more competitive or aggressive than women. There is also a large amount of individual diversity within all these traits and hormone levels.

Clinical relevance

Disorders

Disorders of the hypothalamic–pituitary–gonadal axis are classified by the World Health Organization (WHO) as:[15]

Gene mutations

Genetic mutations and chromosomal abnormalities are two sources of HPG axis alteration.[17] Single mutations usually lead to changes in binding ability of the hormone and receptor leading to inactivation or over activation. These mutations can occur in the genes coding for GnRH, LH, and FSH or their receptors. Depending on which hormone and receptor are unable to bind different effects occur but all alter the HPG axis.

For example, the male mutation of the GnRH coding gene could result in hypogonadotrophic hypogonadism. A mutation that cause a gain of function for LH receptor can result in a condition known as testotoxicosis, which cause puberty to occur between ages 2–3 years. Loss of function of LH receptors can cause male pseudohermaphroditism. In females mutations would have analogous effects. Hormone replacement can be used to initiate puberty and continue if the gene mutation occurs in the gene coding for the hormone. Chromosomal mutations tend to affect the androgen production rather than the HPG axis.

Medications

Medications for diseases, conditions, and personal reasons often take advantage of the HPG axis. By altering hormones levels of the HPG axis, desirable effects can occur often along with side effects. Hormone levels can be altered in the case of hormonal birth control and hormone replacement therapy. Although often described as preventing pregnancy by mimicking the pregnancy state, hormonal birth control is effective because it works on the HPG axis to mimic the luteal phase of a woman's cycle. The primary active ingredients are synthetic progesterones, which mimic biologically derived progesterone. The synthetic progesterone prevent the hypothalamus from releasing GnRH and the pituitary from releasing LH and FSH; therefore it prevents the ovarian cycle from entering the menstrual phase and prevents follicle development and ovulation. Also as a result, many of the side effects are similar to the symptoms of pregnancy. Hormone replacement therapy disrupt the HPG axis decline but focus more on estrogen. Alzheimer's has been shown to have a hormonal component, which could possibly be used as a method to prevent the disease.[18]

Environment factors

Environment can have large impact on the HPG axis. One example is women with eating disorders suffer from oligomenorrhea and secondary amenorrhea. Starvation from anorexia nervosa or bulimia causes the HPG axis to deactivate causing women's ovarian and uterine cycles to stop. Stress, physical exercise, and weight loss have been correlated with oligomenorrhea and secondary amenorrhea.[19] Similarly environmental factors can also affect men such as stress causing impotence. Prenatal exposure to alcohol can affect the hormones regulating fetal development resulting in foetal alcohol spectrum disorder.[20]

Comparative anatomy

The HPG axis is highly conserved in the animal kingdom.[21] While reproductive patterns may vary, the physical components and control mechanisms remain the same. The same hormones are used with some minor evolutionary modifications. Much of the research is done on animal models, because they mimic so well the control mechanism of human. It is important to remember humans are the only species to hide their fertile period, but this effect is a difference in the effect of the hormones rather than a difference in the HPG axis. Research about the evolution of the HPG axis can help to better treat conditions of the HPG axis.

See also

References

  1. ^ Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR (April 2004). "Gonadotropin-releasing hormone receptors". Endocr. Rev. 25 (2): 235–75. doi:10.1210/er.2003-0002. PMID 15082521.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Charlton H (June 2008). "Hypothalamic control of anterior pituitary function: a history". J. Neuroendocrinol. 20 (6): 641–6. doi:10.1111/j.1365-2826.2008.01718.x. PMID 18601683.
  3. ^ Vadakkadath Meethal S, Atwood CS (February 2005). "The role of hypothalamic-pituitary-gonadal hormones in the normal structure and functioning of the brain". Cell. Mol. Life Sci. 62 (3): 257–70. doi:10.1007/s00018-004-4381-3. PMID 15723162.
  4. ^ Meethal SV, Liu T, Chan HW, Ginsburg E, Wilson AC, Gray DN, Bowen RL, Vonderhaar BK, Atwood CS (August 2009). "Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors". J. Neurochem. 110 (3): 1014–27. doi:10.1111/j.1471-4159.2009.06192.x. PMC 2789665. PMID 19493163.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1093/humupd/dmt033, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1093/humupd/dmt033 instead.
  6. ^ http://www.ncbi.nlm.nih.gov/pubmed/19576263
  7. ^ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528850/
  8. ^ http://www.ncbi.nlm.nih.gov/pubmed/16469799
  9. ^ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528850/
  10. ^ a b Katja Hoehn; Marieb, Elaine Nicpon (2007). Human anatomy & physiology. San Francisco: Pearson Benjamin Cummings. pp. 1090–1110. ISBN 0-8053-5909-5.{{cite book}}: CS1 maint: multiple names: authors list (link)
  11. ^ a b Veldhuis JD, Keenan DM, Liu PY, Iranmanesh A, Takahashi PY, Nehra AX (February 2009). "The aging male hypothalamic-pituitary-gonadal axis: pulsatility and feedback". Mol. Cell. Endocrinol. 299 (1): 14–22. doi:10.1016/j.mce.2008.09.005. PMC 2662347. PMID 18838102.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Downs JL, Wise PM (February 2009). "The role of the brain in female reproductive aging". Mol. Cell. Endocrinol. 299 (1): 32–8. doi:10.1016/j.mce.2008.11.012. PMC 2692385. PMID 19063938.
  13. ^ Hines M (July 1982). "Prenatal gonadal hormones and sex differences in human behavior". Psychol Bull. 92 (1): 56–80. doi:10.1037/0033-2909.92.1.56. PMID 7134329.
  14. ^ Shepard KN, Michopoulos V, Toufexis DJ, Wilson ME (May 2009). "Genetic, epigenetic and environmental impact on sex differences in social behavior". Physiol. Behav. 97 (2): 157–70. doi:10.1016/j.physbeh.2009.02.016. PMC 2670935. PMID 19250945.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Page 54 in: Guillebaud, John; Enda McVeigh; Roy Homburg (2008). Oxford handbook of reproductive medicine and family planning. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-920380-6.{{cite book}}: CS1 maint: multiple names: authors list (link)
  16. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1093/humupd/dms019, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1093/humupd/dms019 instead.
  17. ^ Isidori AM, Giannetta E, Lenzi A (2008). "Male hypogonadism". Pituitary. 11 (2): 171–80. doi:10.1007/s11102-008-0111-9. PMID 18404386.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Haasl RJ, Ahmadi MR, Meethal SV, Gleason CE, Johnson SC, Asthana S, Bowen RL, Atwood CS (2008). "A luteinizing hormone receptor intronic variant is significantly associated with decreased risk of Alzheimer's disease in males carrying an apolipoprotein E epsilon4 allele". BMC Med. Genet. 9: 37. doi:10.1186/1471-2350-9-37. PMC 2396156. PMID 18439297.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  19. ^ Wiksten-Almströmer M, Hirschberg AL, Hagenfeldt K (2007). "Menstrual disorders and associated factors among adolescent girls visiting a youth clinic". Acta Obstet Gynecol Scand. 86 (1): 65–72. doi:10.1080/00016340601034970. PMID 17230292.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Weinberg J, Sliwowska JH, Lan N, Hellemans KG (April 2008). "Prenatal alcohol exposure: fetal programming, the hypothalamic-pituitary-adrenal axis and sex differences in outcome". J. Neuroendocrinol. 20 (4): 470–88. doi:10.1111/j.1365-2826.2008.01669.x. PMID 18266938.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Sower SA, Freamat M, Kavanaugh SI (March 2009). "The origins of the vertebrate hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-thyroid (HPT) endocrine systems: new insights from lampreys". Gen. Comp. Endocrinol. 161 (1): 20–9. doi:10.1016/j.ygcen.2008.11.023. PMID 19084529.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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