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Male Prolactin and Hyperprolactinemia

Normal Prolactin
Abnormal Prolactin
Male Prolactin

Male ProlactinMale Prolactin and Hyperprolactinemia

Chanel L. Bonds, Laura E.A. Simon, Stephen E. Hudson, Andrew K. Lee, and William E. Roudebush
Department of Biomedical Sciences, University of South Carolina School of Medicine Greenville
Greenville, South Carolina, USA

Case Introduction

“John” is a 48-year-old male who has been suffering from chronic headaches for the past month. He takes ibuprofen for the headaches, which provide only some relief. He also has difficulty seeing when he is changing lanes while driving. He complains that he has been feeling more tired than usual and does not enjoy some of his regular activities, like golfing, as much as he used to. He also has been having “problems in the bedroom” lately, namely, a lack of interest in sex and difficulty maintaining an erection. John figures he is just “past his prime” but at the request of his wife, he makes a doctor’s appointment.

 

John sees his primary care physician who conducts some testing including blood work and imaging. His results show that John has lower than normal luteinizing hormone, follicle stimulating hormone and testosterone levels. Most noteworthy is that John’s prolactin levels are very high. An MRI confirms what his physician was thinking “hyperprolactinemia due to a prolactinoma”, which is elevated serum prolactin levels resulting from a tumor of the anterior pituitary gland.

 

Prolactin Physiology: The Synthesis, Secretion, and Actions of Prolactin

Prolactin is a hormone made by the anterior pituitary gland in the brain (see figure 1) and is most commonly known as a milk production stimulant in lactating females. Additionally, prolactin plays a role in metabolism, regulating the immune system and acts on sex hormone formation pathways in both sexes. The production and secretion of prolactin by the anterior pituitary gland is a highly regulated process influenced by several hormones, neurotransmitters, and other substances produced in the human body as well as substances consumed in the diet. Prolactin secretion peaks during sleep and dwindles just before noon. The amount of prolactin secreted decreases with advancing age (3).

 

After being released by the anterior pituitary gland, prolactin has several actions throughout the body in a normal, healthy individual. One of actions of prolactin is to influence sex hormone production in the reproductive organs of both sexes. In males, prolactin helps to maintain functionality of the androgen-producing cells (i.e. the Leydig cells) in the testes. Prolactin also acts to directly and indirectly regulate the production of androgens by the testicular Leydig cells which is of critical importance for male fertility (1). An excess of prolactin levels lead to reduced testosterone production and decreased spermatogenesis, which present clinically as diminished libido, impotence and infertility (4). Prolactin also has actions in the kidney and in the immune system which have not yet been clearly linked to fertility. There is also evidence that prolactin may induce REM sleep to some extent (3).

 

Figure 1. The normal pituitary gland.

Normal Prolactin

Pathophysiology

Hyperprolactinemia is defined as increased levels of serum prolactin. Normal prolactin levels are between 5-21 ng/mL. A prolactin level greater than 21 ng/mL is abnormally high (7). Hyperprolactinemia can be high due to normal physiological causes. Physiological or psychological stress can elevate prolactin in both men and women, but values rarely exceed 40 ng/mL. Women generally have higher levels of prolactin than men and also secrete more prolactin in response to physiological triggers than men (6). Strenuous exercise, sleep, and high-protein meals have also shown to increase prolactin levels.

 

There are many pathologic causes of hyperprolactinemia. These causes include a prolactinoma (the most common, see figure 2), other pituitary tumors, tumors of the hypothalamus, cranial trauma, certain medications (for example, antipsychotics), decreased clearance of prolactin by the kidneys, and other diseases (6). When prolactin levels are elevated beyond normal limits, significantly decreased androgen productions can lead to a decrease or even arrest of sperm production, as well as altered quality of sperm. The symptoms associated with these hormone changes include infertility, decreased energy, decreased libido, and erectile dysfunction. Long-term abnormalities can result in decreased muscle mass, body hair, osteopenia, and osteoporosis (2).

 

Prolactinomas

Prolactinomas are prolactin-secreting tumors and the most common cause of hyperprolactinemia in males (see figure 2). These tumors are the most common neoplasms of the pituitary gland, accounting for 30-40% of pituitary adenomas (6). Prolactinomas may arise as a single medical abnormality. However, some also occur in the setting of the familial condition, multiple endocrine neoplasia  type 1. Prolactinomas are usually benign and vary in size. A prolactin level above 200 ng/mL is highly suggestive of prolactinoma. The amount of prolactin secreted by the tumors often correlates with the size of the adenoma. Elevated prolactin levels due to a prolactinoma can range from minimally elevated (e.g. >21 ng/mL) to greater than 50,000 ng/mL (6). While a prolactin level above 200 ng/mL likely indicates a prolactinoma, imaging studies of the head are generally indicated. Magnetic resonance imaging (MRI) should be performed in any patient with hyperprolactinemia unless the cause can be attributed to a medication being taken by the patient (6). Other pituitary hormone levels, such as thyroid stimulating hormone and thyroid hormone, should be tested if a mass is discovered in the pituitary on MRI to evaluate other possible hormone abnormalities caused by the tumor (7).

 

Prolactinomas can arise in men and cause no symptoms. More typically, the production of high prolactin levels can cause symptoms that men are disinclined to share with a physician, such as erectile dysfunction and decreased libido. For this reason, they typically present to a physician late, allowing the tumors to grow larger. If the tumor grows larger than 1 cm, it is known as a macroadenoma. This can lead to symptoms associated with “mass effect,” such as headaches and visual defects (5). Men often do not seek medical attention for symptoms associated with a prolactinoma until after a tumor has exceeded 1cm in diameter. A macroadenoma can become large enough to grow out of the sella turcica, the structure in which the pituitary gland sits, and the compress the optic chiasm (see figure 2), where the optic nerves from each eye cross. Lesions of the optic chiasm can cause visual losses, specifically losses of the temporal visual fields, known as bitemporal hemianopsia. Men with macroadenomas compressing the optic chiasm can present with visual blurring or losses in this pattern in one or both of the eyes (8).

 

Figure 2. Abnormal Pituitary-Prolactinoma

Abnormal Prolactin

Treatment

Treatment is indicated when patients are experiencing symptomatic hormone imbalances or neurologic symptoms, such as vision changes and headaches. First line treatment is typically medical management using prolactin inhibiting drugs like bromocriptine and carbergoline. These agents indirectly decrease prolactin levels and can considerably reduce the size of prolactin tumors in the pituitary. Other treatments may need to be considered, depending on the individual health conditions of each patient (6). Larger tumors causing mass effect or tumors unresponsive to pharmacologic therapy or hemorrhaged tumors may require surgery. Surgery is generally successful in lowering prolactin levels, but all of the adenoma tissue may not be excised, especially if the tumor is large, and the adenoma might recur (9).

Acknowledgements

The authors thank Dr. Bruce B. Latham, Endocrinology Specialists, Greenville Health Systems, Greenville, SC for his valuable technical editing and to Lindsey Brown, Web Developer, University of South Carolina School of Medicine Greenville for her development of the medical images (Figures 1 and 2).

References

1.Bole-Feysot, Christine; Goffin, V.; Edery, M.; Binart, N.; Kelly, P. A. “Prolactin (PRL) and Its Receptor: Actions, Signal Transduction Pathways and Phenotypes Observed in PRL Receptor Knockout Mice.” Endocrine Reviews 1998;19-3:225-268.

  1. Di Somma C, Colao A, Di Sarno A, Klain M, Landi ML, Facciolli G, Pivonello R, Panza N, Salvatore M, Lombardi G. Bone marker and bone density responses to dopamine agonist therapy in hyperprolactinemic males. J Clin Endocrinol Metab. 1998;83(3):807
  2. Melmed, Shlomo; Polonsky, Kenneth S.; Larsen, P. Reed; Kronenberg, Henry M.  “Pituitary Physiology and Diagnostic Evaluation.” in Williams Textbook of Endocrine Physiology, Twelfth Edition, 2008:175-228.
  3. Javorsky BR, Aron DC, Findling JW, Tyrell JB. “Hypothalamus and Pituitary Gland.” in Greenspan’s Basic & Clinical Endocrinology, 9th Edition, 2011: 80-82.
  4. Singh, Pratibha, Manish Singh, Goutham Cugati, Ajai Kumar Singh. J Hum Reprod Sci. 2011;4(2):102–103.
  5. Snyder, Peter. Causes of hyperprolactinemia. UpToDate. Updated Jul 18, 2014.
  6. Snyder, Peter. Clinical manifestations and evaluation of hyperprolactinoma. UpToDate. Updated Aug 13, 2014.
  7. Snyder, Peter. Clinical manifestations and diagnosis of gonadotroph and other clinically nonfunctioning pituitary adenomas. UpToDate. Updated Dec 09, 2014.
  8. Snyder, Peter. Treatment of hyperprolactinemia due to lactotroph adenoma and other causes. UpToDate. Updated Feb 4, 2014.

The Male Reproductive System: Sperm Analysis

Sperm Analysis

Take this mini course on the Male Reproductive System and test your anatomy knowledge at the same time.

Laura E. A. Cook, M.D., Jan A. Enabore, and
William E. Roudebush, Ph.D, HCLD

Department of Biomedical Sciences
University of South Carolina School of Medicine Greenville
Greenville, SC, USA

The male reproductive system structures give men the ability to reproduce by fertilizing a woman’s egg. There are a number of organs that make up the male reproductive system.
Although infertility is commonly felt to be a female condition, a male factor often plays a significant role. Certain risk factors place a male at higher risk of having infertility including any abnormalities or issues with the testicles themselves, prior treatment for cancer, hormonal disorders, prior scrotal surgery, or even infections such a sexually transmitted disease.

 

The Function of Endogenous Platelet Activating Factor (PAF) in Human Sperm

Blackboard with MALE INFERTILITY on it

by

Slee L. Yi1, Julia M. Robison1, and William E. Roudebush1,2

1University of South Carolina School of Medicine Greenville, 2Fertility Center of the Carolinas, Department of Obstetrics & Gynecology,
Greenville Health System, Greenville, South Carolina

 

Eight to ten million couples are afflicted with infertility in the United States. Infertility can be caused by a number of factors. Not only females but also males can have problems with infertility. Male infertility is the primary culprit in ~25% of these couples, and is a factor in additional 20% of these couples. There are several prerequisites that must be met for male fertility. Defects in any of these will result in infertility.1

Platelet Activating Factor

Platelet-activating factor, commonly known as PAF, is a phospholipid involved in a number of biological activities. PAF was first discovered and studied in rabbits over thirty years ago.2 It is known to be present in several mammalian species including mice, bulls, boars, and even humans.1,3-5 Since its discovery, PAF has been found to play a significant role in reproductive physiology.1

Research shows that PAF plays a very important role in sperm motility. It does this through binding to PAF receptors found in the sperm membrane.  Reports indicate that PAF receptors exist at the midpiece (neck) and the equatorial (head) regions of the sperm. Binding at these locations leads to an increase in fertility rate. Conversely, when these receptors are abnormal or appear at abnormal locations, fertility is compromised.1,6

During the last few years, scientists have discovered different amounts of PAF and PAF receptors in motile and non-motile sperm. Studies have found that motile sperm contain a greater number of PAF receptors than do non-motile sperm.  Interestingly as well, the actual PAF concentration in motile sperm appears to be less compared to non-motile sperm. This indicates that non-motile sperm contain more PAF than motile sperm because they are not able to use it. Motile sperm shows less PAF content because these cells are using it.1,7 Fertility may be further compromised in the presence of PAF antagonists.  These are substances that compete against PAF at the receptor site, which causes a decrease in PAF binding and can resuls in infertility. Although the exact mechanism for this is unclear, its importance is substantial. 1,8-10

The active form of PAF is produced inside the male sperm cell through a cycle of reactions. The enzyme responsible for synthesizing active PAF is also found in the sperm cell itself.1,11 However, there are enzymes that disable PAF by converting it into an inactive form.1,12These disabling agents are present in seminal fluid.13 The process therefore requires sperm to be separated from the seminal fluid in order for PAF to become active and cause increased sperm motility. This separation occurs when sperm is ejaculated – typically into the vagina, where it will swim away from the fluid and enter the uterus. Once sperm is separated from the seminal fluid, PAF can be synthesized and subsequently bind to its receptors on the sperm cell membrane. Once the sperm responds to PAF, its motility dramatically increases, and it becomes ready to fertilize the egg.14 This process is called capacitation. As expected, sperm cells that have not yet capacitated are found to contain lower levels of PAF.1,12 That is because, as explained, the seminal fluid contains substances which prevent active PAF from being synthesized. On the other hand, capacitated sperm cells are found to contain higher levels of PAF. When active PAF is present in the sperm cell and is able to appropriately bind to its receptors, it improves interactions between sperm and egg, and positively affects pregnancy outcomes.1 Determining the active PAF content and its interaction with receptors could potentially be a beneficial diagnostic tool for male infertility. Further research should be conducted to better understand PAF and how PAF could possibly be useful in clinical applications such as in vitro fertilization (IVF) in the near future.1,15

 

References

1. Roudebush WE. Seminal platelet-activating factor. Semin Throm Hemost 2007;33:69-74

2. Benveniste J, Henson PM, Cochrane CG. Leukocyte dependent histamine release from rabbit platelets: the role of Ig-E, basophils, and platelet-activating factor. J Exp Med 1972;136:1356–1376
3. Parks JE, Hough S, Elrod C. PAF activity in bovine sperm. Biol Reprod 1990;43:806–811
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4. Minhas BS, Kumar R, Ricker DD, Robertson JL, Dodson MG. The presence of platelet activating factor-like activity in human sperm. Fertil Steril 1991;55:372–376
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5. Mook JL, Diehl JR, Mathur RS, Roudebush WE. Presence of platelet-activating factor in porcine sperm and uterine fluid. Theriogenology 1998;49:351
6. Harper MJK. Platelet activating factor: a paracrine factor in 
preimplantation stages of development? Biol Reprod 1989; 40: 907–913

7. Purnell ET, Roudebush WE. Platelet-activating factor activity levels (ligand and receptor transcript content in sperm: motile versus nonmotile. In: Proceedings of the VIIth International Congress of Andrology. Montreal, Quebec: Andrology in the 21st; 2001:71-76.

8. Reinhardt JC, Cui X, Roudebush WE. Immunofluorescent evidence of the platelet-activating factor receptor on human spermatozoa. Fertil Steril 1999;71:941–942
9. Roudebush WE, Ito C, Purnell E, Cui X. Presence of platelet-activating factor and its receptor in baboon (Papio spp) spermatozoa. Int J Primatol 1999;20:273–280
10. Roudebush WE, Wild MD, Maguire EH. Platelet-activating factor receptor expression in human sperm: differences in mRNA content and protein distribution between normal and abnormal sperm. Fertil Steril 2000;73:967–971

11. Bennet PJ, Moatti JP, Mansat A, et al. Evidence for the activation of phospholipases during acrosome reaction of human sperm elicited by calcium ionophore A23187. Biochim Biophys Acta 1987;919:255–265

12.  Letendre ED, Miron P, Roberts KD, Langlais J. Platelet- activating factor acetylhydrolase in seminal plasma. Fertil Steril 1992;57:193–198

13. Gujarati VR, Naukam RJ, RamaSastry BV. Enzymatic deacetylation and acetylation of ether phospholipids related to platelet-activating factor in human semen with short and long liquefaction times. Ann N Y Acad Sci, 1987, 513:583–585.

14. Davis BK. Timing of fertilization in mammals: Sperm cholesterol/phospholipid radio as a determinant of the capacitation interval. Proceedings National Academy of Sciences of the United States of America. 1981, 78:7560-7564.

15. Toledo AA, Mitchell-Leef D, Elsner CW, Slayden SM, Roudebush WE. Fertilization potential of human sperm is correlated with endogenous platelet-activating factor content. J Assist Reprod Genet 2003; 20:192–195.