**Prolactin and Infertility**

Gokalp Oner

146 Prolactin

[25] Furudate S, Nakano T (1989) Prolactin Secretion and its Response to Stress during the

Estrous Cycle of the Rats. Exp. anim. 38: 313-318.

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55557

#### **1. Introduction**

Prolactin (PRL) is one of several hormones that are produced by the pituitary gland. PRL has many different roles throughout the body, and most of those are clearly shown as clinical symptom. Perhaps the most important classical role of prolactin is to stimulate milk production in women after the delivery of a baby. Prolactin levels increase during pregnancy causing the mammary glands to enlarge in preparation for breastfeeding and ready to secrete colostrums closely after delivery. Later on the elevated prolactin levels help with the sustained production of milk during nursing. The somatomammotrop cells of the anterior pituitary gland synthesize and secrete prolactin, which is under the control of hypothalamic factors, mainly the tonic inhibition of Dopamine (DA). There are several other sources of PRL-like substances in the periphery such as placental lactogens, (similar to pituitary PRL), mammary gland (produced within the mammary epithelial cells), or PRL variants of immune cell origin (that modulates the immune system). (Gellersen,1989; Andersen 1990; Lkhider, 1996; Kurtz,1993; Gala, 1994, Montgomery,1990; Ben-Jonathan 1996; Yu-Lee LY 1997)

It is important to underline that serum PRL in normal individuals is considered as almost entirely pituitary PRL sources, the above mentioned extra pituitary-PRL may contribute significant amounts but either carries as specific function and target mainly to the local environment acting via paracrine/autocrine manner. (Yu-lee 1997; Bachelot 2007)

During the first several months of breastfeeding, the higher basal prolactin levels also serve to suppress ovarian cyclicity , through the inhibition of pituitary hormones, mainly via LH suppression (Taya 1982) This is the reason why women who are breastfeeding do not get their periods and therefore do not often become pregnant. In actively breastfeeding mothers the related hyperprolactinaemia persisting even over a year. It was observed that extended lactational amenorrhea is associated with low LH levels, and interestingly suckling induced PRL elevation as a response has a positive effect on prolongation. (Diaz 1991; Diaz 1995).

© 2013 Oner, 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, and reproduction in any medium, provided the original work is properly cited.

Menstruation and ovulation may only occasionally occur before the drop of elevated basal PRL levels. As time goes on with less frequent breastfeeding, e.g. during weaning however, the PRL levels do not stay as high and the woman may start to ovulate. In cases of nonlactating/ nonbreastfeeding mothers, that may happen between 2-3 month after delivery. (Baird 1979)

Prolactin and Infertility 149

Hyperprolactinemia is commonly found in both female and male patients with abnormal sexual and/or reproductive function or with galactorrhea. If serum prolactin levels are above 200 μg/L, a prolactin-secreting pituitary adenoma (prolactinoma) is the underlying cause, but if levels are lower, differential diagnoses include the intake of various drugs, compression of the pituitary stalk by other pathology, hypothyroidism, renal failure, cirrhosis, chest wall lesions, or idiopathic hyperprolactinemia. When a pituitary tumour is present, patients often have pressure symptoms in addition to endocrine dysfunction, such as headaches, visual field defects, or cranial nerve deficits (Wang, 2012). The objectives of therapy are to improve the symptoms associated with high PRL levels and to reduce the size

Pharmacotherapy is available to reduce the tumour size and consequently decrease PRL levels. The large majority of patients with prolactinomas, both micro- and macroprolactinomas, can be successfully treated with dopamine D2 receptor agonists as first-line treatment, with normalization of prolactin secretion and gonadal function, and with significant tumour shrinkage in a high percentage of cases, to prevent the need for surgery. In cases when the only cause of infertility is chronic anovulation due to hyperprolactinemia, a 60-80% pregnancy rate can be achieved. Surgical resection of the prolactinoma is the option for patients who may refuse or do not respond to long-term pharmacological therapy. Radiotherapy and/or estrogens are also reasonable choices if surgery fails. In patients with asymptomatic microprolactinoma no treatment needs to be given and a regular follow-up with serial prolactin measurements and pituitary imaging

The most commonly used dopamine agonists are bromocriptine, pergolide, quinagolide and cabergoline. When comparing the plasma half-life, efficacy and tolerability of these drugs are different, there is also important to evaluate the risk/ benefits profile of each product. As the current clinical practice, pharmacological treatment with dopamine agonist plays an important role. The recommendations on the most effective dosages and the advantages of a long term efficacy of products have been evaluated summarizing the results of case histories

A variety of etiological factors including disorders of the hypothalamo-pituitary axis, interruption of dopamine synthesis, stress, pituitary tumours, polycystic ovary syndrome, primary hypothyroidism, and various medications may lead to hyperprolactinemia (5). Hyperprolactinemia in girls causes delayed puberty, hypogonadotropic hypogonadism, primary or secondary amenorrhea, and galactorrhea (Fideleff, 2000). Hyperprolactinemia in men may result in as a first signs of decreased libido or impotence, however also cause

As one of the fist signs in women with high prolactin levels may have irregular periods or no periods at all. Another common symptom is "galactorrhea", which is the occurrence of a milky discharge from the breast in a woman who has not recently been pregnant. The

should be organized (Asa 2002; Crosignani 1999, Molitch 2003).

**2. Clinical diagnosis of hyperprolactinemia** 

inefficient sperm production and infertility (Colao, 2004).

of a pituitary tumour.

of the last decades.

Similarly, elevated PRL levels are shown during gestation, but mechanisms to inhibit ovulation is related to elevated estardiol and progesterone levels and a consequent depression of pituitary FSH secretion (Marrs 1981).

Generally, the lactogenic hormones play role also in regulation of reproductive function. On one hand, PRL is essential to maintain regular oestrus cycles. PRL knock out mice are completely infertile (Horsemann 1997). One of the other actions of PRL is to stimulate ovarian production of progesterone. That is required in the process of preparation for embryo implantation and it is dependent on a continued estrogen and progesterone secretion by the corpus luteum, which is supported by a functional pituitary during the first half of pregnancy in rodents. (Binart 2000)

On the other hand, high prolactin levels are associated with anovulation or may cause directly or indirectly infertility. In young women, hyperprolactinemia is probably one of the most common endocrine disorders related to pituitary function. Women who are not pregnant and are not breastfeeding should have lower levels of basal PRL (typically 10–28 μg/L in women and 5–10 μg/L in men are defined as "normal levels") If a non-pregnant woman has abnormally high levels of PRL, it may cause her difficulty in becoming pregnant. It is considered as the most frequent cause of anovulatory sterility, although spontaneous pregnancy may occur occasionally. The prevalence of hyperprolactinemia varies in different patient populations, stays below 1% (0.4% in an unselected normal population) but can be as high as 17% of women with reproductive disorders shown at the clinics (Crosignani 1999)

The suppression of pituitary hormones by PRL, similar that described during lactation has an indirect anovulatory effect. PRL however, acts also directly on the ovary to inhibit the hCG-induced follicle rupture, resulting in the inhibition of ovulation. (Yoshimura 1989).

Clinically significant elevation of PRL levels may cause infertility in several different ways. First, prolactin may stop a woman from ovulating. If this occurs, a woman's menstrual cycles will stop. In less severe cases, high prolactin levels may only disrupt ovulation once in a while. This would result in intermittent ovulation or ovulation that takes a long time to occur. Women in this category may experience infrequent or irregular periods. Women with the mildest cases involving high prolactin levels may ovulate regularly but not produce enough of the hormone progesterone after ovulation. This is known as a luteal phase defect. Deficiency in the amount of progesterone produced after ovulation may result in a uterine lining that is less able to have an embryo implant. Some women with this problem may see their period come a short time after ovulation (Shibli-Rahhal,2011)

Hyperprolactinemia is commonly found in both female and male patients with abnormal sexual and/or reproductive function or with galactorrhea. If serum prolactin levels are above 200 μg/L, a prolactin-secreting pituitary adenoma (prolactinoma) is the underlying cause, but if levels are lower, differential diagnoses include the intake of various drugs, compression of the pituitary stalk by other pathology, hypothyroidism, renal failure, cirrhosis, chest wall lesions, or idiopathic hyperprolactinemia. When a pituitary tumour is present, patients often have pressure symptoms in addition to endocrine dysfunction, such as headaches, visual field defects, or cranial nerve deficits (Wang, 2012). The objectives of therapy are to improve the symptoms associated with high PRL levels and to reduce the size of a pituitary tumour.

Pharmacotherapy is available to reduce the tumour size and consequently decrease PRL levels. The large majority of patients with prolactinomas, both micro- and macroprolactinomas, can be successfully treated with dopamine D2 receptor agonists as first-line treatment, with normalization of prolactin secretion and gonadal function, and with significant tumour shrinkage in a high percentage of cases, to prevent the need for surgery. In cases when the only cause of infertility is chronic anovulation due to hyperprolactinemia, a 60-80% pregnancy rate can be achieved. Surgical resection of the prolactinoma is the option for patients who may refuse or do not respond to long-term pharmacological therapy. Radiotherapy and/or estrogens are also reasonable choices if surgery fails. In patients with asymptomatic microprolactinoma no treatment needs to be given and a regular follow-up with serial prolactin measurements and pituitary imaging should be organized (Asa 2002; Crosignani 1999, Molitch 2003).

The most commonly used dopamine agonists are bromocriptine, pergolide, quinagolide and cabergoline. When comparing the plasma half-life, efficacy and tolerability of these drugs are different, there is also important to evaluate the risk/ benefits profile of each product. As the current clinical practice, pharmacological treatment with dopamine agonist plays an important role. The recommendations on the most effective dosages and the advantages of a long term efficacy of products have been evaluated summarizing the results of case histories of the last decades.
