**11. Recommendations for resistant, malignant prolactinoma**

Specific recommendations for management of resistant and malignant prolactinoma are as follows (Melmed 2011):


### **12. Recommendations for pregnant women with prolactinoma**

160 Prolactin

of taking them orally.

instead of every day.

tumours.

follows (Melmed 2011):

surgery.

**9.2. Cabergoline (Dostinex)** 

drive, and bone loss, are listed.

can be stopped upon diagnosis of pregnancy. However, if a woman has a macroadenoma,

Due to the side effects, some women can not tolerate Parlodel. For these women, they may try alternatives, e.g. vaginal bioadhesive suppositories or inserted the pills vaginally instead

Because it is more expensive, cabergoline is not usually the first choice for treatment of high prolactin levels. It is usually used when Parlodel is ineffective or a woman cannot tolerate the side effects. Cabergoline is a longer acting medication. It is usually given twice a week

The Endocrine Society has released a new clinical practice guideline for the diagnosis and treatment of patients with hyperprolactinemia (Melmed, 2011). The new recommendations for management of elevated levels of the PRL, which is associated with infertility, low sex

Specific recommendations for management of prolactinoma are as follows (Melmed 2011):: Dopamine agonist therapy is recommended to reduce prolactin levels and tumor size and to restore gonadal function in patients with symptomatic prolactin-secreting microadenomas or macroadenomas. Compared with other dopamine agonists, cabergoline is more effective in normalizing prolactin levels and in shrinking pituitary

 Dopamine agonists are not recommended for asymptomatic patients with microprolactinomas. However, patients with microadenomas who have amenorrhea

 In patients treated with dopamine agonists for at least 2 years who no longer have elevated serum prolactin levels or visible tumour on MRI, careful clinical and

Specific recommendations for management of resistant and malignant prolactinoma are as

 For symptomatic patients in whom normal prolactin levels are not achieved or who have significant shrinking of the tumour size while receiving standard doses of a dopamine agonist, the dose should be increased rather than referring the patient for

biochemical follow-up therapy may be tapered and perhaps discontinued.

Parlodel should be continued through pregnancy and delivery.

**10. Recommendations for the treatment of prolactinoma** 

can be treated with a dopamine agonist or oral contraceptives.

**11. Recommendations for resistant, malignant prolactinoma** 

Patients resistant to bromocriptine should be switched to cabergoline.

Specific recommendations for management of prolactinoma during pregnancy are as follows (Melmed 2011):


Hyperprolactinemia has been proposed to block ovulation through inhibition of GnRH release. Kisspeptin neurons, which express prolactin receptors, were recently identified as major regulators of GnRH neurons. A recently published study demonstrated that hyperprolactinemia in mice induced anovulation, reduced GnRH and gonadotropin secretion, and diminished kisspeptin expression. Kisspeptin administration restored gonadotropin secretion and ovarian cyclicity, suggesting that kisspeptin neurons play a major role in hyperprolactinemic anovulation. This study indicate that administration of kisspeptin may serve as an alternative therapeutic approach to restore the fertility of hyperprolactinemic women who are resistant or intolerant to dopamine agonists (Sonigo, 2012).

To sum up, the systematic reviews and meta-analyses affirm the use of dopamine agonists in treating hyperprolactinemia and reducing associated morbidity. Cabergoline was found to be more effective than bromocriptine in achieving normoprolactinemia and resolving amenorrhea/oligomenorrhea and galactorrhea. Radiotherapy and surgery are efficacious in patients with resistance or intolerance to dopamine agonists (Wang, 2012).

#### **13. Summary**

*Hyperprolactinemia* is defined as higher-than-normal blood levels of the hormone prolactin. This hormone is made by the pituitary gland, which is located at the base of the brain. The main function of prolactin is to stimulate breast milk production after childbirth. High prolactin levels are normal during pregnancy and breastfeeding. In other cases, prolactin can become too high because of a disease or the use of certain medications. Often, the cause is a prolactin-producing tumour in the pituitary gland, called a *prolactinoma*. This tumour is mostly benign (adenomas), meaning **not** invasive (invasive tumours with multiple recurrences are "atypical adenomas"), and not metastatic (malignant tumours, carcinomas). It is more common in women than men. Rarely, children and adolescents develop prolactinomas. Other brain tumours may also cause the pituitary gland to make too much prolactin.

Prolactin and Infertility 163

Ben-Jonathan N, Mershon JL, Allen DL & Steinmetz RW 1996 Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects. Endocrine Review 17 639–669. Binart N, Helloco C, Ormandy CJ, Barra J, Clement-Lacroix P, Baran N & Kelly PA 2000 Rescue of preimplantatory egg development and embryo implantation in prolactin receptor-deficient mice after progesterone administration. Endocrinology 141 2691–

Bracero N, Zacur HA. Polycystic ovary syndrome and hyperprolactinemia. Obstet Gynecol

Buurman H, Saeger W 2006 Subclinical adenomas in postmortem pituitaries: classification

Cepický P, Sulková S, Stroufová A, Roth Z, Burdová I. The correlation of serum prolactin level and psychic stress in women undergoing a chronic hemodialysis programme. Exp

Colao A, Loche S, Cappa M, Di Sarno A, Landi ML, Sarnacchiaro F, Facciolli G, Lombardi G. Prolactinomas in children and adolescents. Clinical presentation and long-term follow-

Colao A, Vitale G, Di Sarno A, Spiezia S, Guerra E, Ciccarelli A & Lombardi G 2004 Prolactin and prostate hypertrophy: a pilot observational, prospective, case-control study in men with prolactinoma. Journal of Clinical Endocrinology and Metabolism 89 2770–2775. Crosignani PG. Management of hyperprolactinemia in infertility. J Reprod Med. 1999

Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A 2006 High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege,

Díaz S, Cárdenas H, Brandeis A, Miranda P, Schiappacasse V, Salvatierra AM, Herreros C, Serón-Ferré M, Croxatto HB. Early difference in the endocrine profile of long and short lactational amenorrhea. J Clin Endocrinol Metab. 1991 Jan;72(1):196-201. PubMed

Díaz S, Seron-Ferre M, Croxatto HB, Veldhuis J. Neuroendocrine mechanisms of lactational infertility in women. Biol Res. 1995;28(2):155-63. Review. PubMed PMID: 9251745. Dworakowska D, Grossman AB. The molecular pathogenesis of pituitary tumors: implications for clinical management. Minerva Endocrinol. 2012 Jun;37(2):157-72.

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Prolactin-secreting pituitary tumours are a common cause of amenorrhea and infertility in premenopausal women. The goals of therapy are to normalize prolactin, restore gonadal function and fertility, and reduce tumour size, and dopamine agonists are the preferred therapy. Clinically significant tumour enlargement during pregnancy is uncommon and dependent on tumour size and pre-pregnancy treatment.

Accroding to over 180 clinical study reports (across 3000 patients) treatment with bromocriptine or with cabergoline are both effective in normalization of prolactin levels and also successful in restoration of fertility over 53% of patients. Cabergoline was shown more effective than bromocriptine in persistent hyperprolactinemia, and reducing the symptoms of amenorrhea/oligomenorrhea. At our institution patients with symptomatic prolactinomas, both micro- and macroadenomas, are treated with cabergoline as the firstline approach. In the small group of patients who do not respond to this treatment, or who refuse long-term therapy, surgery is offered. Radiotherapy is given if both pharmacologic therapy and surgery fail.

#### **Author details**

Gokalp Oner *Yozgat Bogazlyan State Hospital, Turkey* 

#### **14. References**


Ben-Jonathan N, Mershon JL, Allen DL & Steinmetz RW 1996 Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects. Endocrine Review 17 639–669.

162 Prolactin

**13. Summary** 

therapy and surgery fail.

*Yozgat Bogazlyan State Hospital, Turkey* 

PubMed PMID: 479342.

pregnancy Dan Med Bull 37: 154-165,1990.

**Author details** 

**14. References** 

Review.

Gokalp Oner

*Hyperprolactinemia* is defined as higher-than-normal blood levels of the hormone prolactin. This hormone is made by the pituitary gland, which is located at the base of the brain. The main function of prolactin is to stimulate breast milk production after childbirth. High prolactin levels are normal during pregnancy and breastfeeding. In other cases, prolactin can become too high because of a disease or the use of certain medications. Often, the cause is a prolactin-producing tumour in the pituitary gland, called a *prolactinoma*. This tumour is mostly benign (adenomas), meaning **not** invasive (invasive tumours with multiple recurrences are "atypical adenomas"), and not metastatic (malignant tumours, carcinomas). It is more common in women than men. Rarely, children and adolescents develop prolactinomas. Other

Prolactin-secreting pituitary tumours are a common cause of amenorrhea and infertility in premenopausal women. The goals of therapy are to normalize prolactin, restore gonadal function and fertility, and reduce tumour size, and dopamine agonists are the preferred therapy. Clinically significant tumour enlargement during pregnancy is uncommon and

Accroding to over 180 clinical study reports (across 3000 patients) treatment with bromocriptine or with cabergoline are both effective in normalization of prolactin levels and also successful in restoration of fertility over 53% of patients. Cabergoline was shown more effective than bromocriptine in persistent hyperprolactinemia, and reducing the symptoms of amenorrhea/oligomenorrhea. At our institution patients with symptomatic prolactinomas, both micro- and macroadenomas, are treated with cabergoline as the firstline approach. In the small group of patients who do not respond to this treatment, or who refuse long-term therapy, surgery is offered. Radiotherapy is given if both pharmacologic

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**Chapter 10** 

© 2013 Nagy et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**The Regulation of Pituitary Prolactin Secretion:** 

A consensus view developed over the last decades holds that the basal secretion of PRL from the anterior lobe (AL) is spontaneous (i.e., occurs without stimulation by the hypothalamus) (Neill 1994; Freeman 2000) since PRL is secreted from lactotropes with a high secretory rate for prolonged periods after disconnecting the hypothalamic influence (when it transplanted to a site distant from the hypothalamus under the kidney capsule or when cultured in vitro). Consequently, PRL secretion appears to be severely restrained by the hypothalamus in vivo as the main source prolactin inhibiting factor (PIF). Results of the extensive research of the last decades have clearly demonstrated that the withdrawal of DA tone is not sufficient to account for the surge of PRL secretion observed in response to the suckling (physiological) stimulus during lactation. Similarly, DAerg tone would not completely recover the chronic elevation of PRL during pregnancy, lactation or in other pathophysiological stages. The research has subsequently included the search for putative prolactin-releasing factors (PRF) controlling PRL peaks occurring after mating or triggered by ovarian steroids. These can be termed by central (i.e hypothalamic) or peripheral (within the pituitary gland) sites of actions. However, it may be better to classify them by the levels of control mechanisms to regulate PRL secretion: *(i)* action on hypothalamic DAerg neurons; *(ii)* binding to specific receptors on lactotrophs in the

i. The hypothalamic regulating factors acting on *hypothalamic DAergic neurons* may have direct activation or inhibition of their activity, or alter DA, resulting in a consequent changes in PRL secretion (Freeman, 2000; Ben-Jonathan, 2008). The final common pathways of the central stimulatory and inhibitory control are the neuroendocrine neurons producing DA available to be delivered into the hypophyseal portal vessels or

and reproduction in any medium, provided the original work is properly cited.

**Hypothalamic, Intrapituitary and Intracellular** 

**Factors and Signaling Mechanisms** 

Viktória Reinhoffer, Márk Oláh, Miklós Vecsernyés,

Additional information is available at the end of the chapter

pituitary gland; *(iii)* paracrine/autocrine compounds.

Béla E. Tóth and György M. Nagy

http://dx.doi.org/10.5772/55571

**1. Introduction** 

