2153 Prolactin antagonists

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Pharmacology and toxicology

Infertility resulting from hyperprolactinemia is reversible after treatment with centrally acting dopamine agonists. Among these, bromocriptine, cabergoline, lisuride, metergoline, and quinagolide are Ihe more frequently used in Ihe clinic.

In a study of 2587 pregnancies in which bromocriptine was administered during the first weeks of pregnancy, there was a slight increase in the rate of early miscarriage but no increase in the rate of birth defects (Krupp 1987). Because most women stop therapy as soon as pregnancy is confirmed, this study also suggests that continuing hyperprolactinemia has no adverse effects on the fetus. A more recent report concerning 27 pregnancies also demonstrated effectiveness and apparent lack of adverse effect of continuing therapy for micro- or macroprolaetinoma with bromocriptine or lisuride through early pregnancy. If, during the course of the pregnancy, ophthalmologic problems occur in connection with macro-prolactinoma, restarting medication therapy is recommended (Ventz 1996). In individual cases, long-term therapy throughout pregnancy is sitmrtimes indicated.

Cabergoline(=jch only needs to be taken once or twice a week because of itsHong-lasting effectiveness, gave no indication of increasing the risk of birth defects in more than 350 pregnancies, which occurred during this therapy. In a few of these pregnancies, treatment was continued throughout pregnancy (de Turris 2003, Kicci 2002, Liu 2001, Verhelst 1999, Ciccarelli 1997, Jones 1997, Robert 1996).

In nine pregnancies, women were treated with quinagolide because their prolactinomas were resistant to bromocriptine. No increase in abnormal outcomes was noted; in four cases treatment was continued throughout pregnancy (Morange 1996). The manufacturer is aware of 176 pregnancies in which quinagolide was continued for a median duration of 37 days. No increase was observed in the complication rate during pregnancy, and no indication for an increase in teratogenic risk was reported (Webster 1996). __

Based on comparative studies, cabcrgolinc and quinagolidej=J11 to be more effective and better tolerated than bromocriptmcin patients with hyperprolactinemia (Barlier 2006, Colao 2000, Schultz 2000, Biller 1999, Webster 1994. van der Heijden 1991).

Documented experience with the use of lisuride and metergoline during pregnancy is insufficient for a risk assessment, although in the scanty published information there is no evidence of risk (Falsetti 1982).

Recommendation. As a result of extensive testing, bromocriptine has been considered the dopamine agonist of choice for hyperprolactinemic amenorrhea. However, presently cabergoline and quinagolide could be considered good treatment options (especially in women with bromocriptine intolerance), given that they seem to be more effective and better tolerated than bromocriptine and have not been associated with any detrimental effect on pregnancy or birth defects. After conception, the medication should, as a rule, be discontinued. However, continuing treatment with it is not grounds for termination of pregnancy or for invasive diagnostic procedures. This recommendation regarding pregnancy exposure also applies to the use of lisuride and metergoline.

2.15.4 Posterior pituitary hormones

Pharmacology and toxicology

Oxytocin and vasopressin are released from the neurohypophysis, Ihe posterior lobe of the pituitary. Structurally speaking, these octapeptide hormones are similar to the hypothalamic hormones.

Oxytocin produces contraction of the uterine muscle and the myoepithelial cells in the breast. During pregnancy, it is produced physiologically in increasing amounts; at the same time, it is inactivated by a similarly increased synthesis of the so-called pregnancy oxytocinase. A role for oxytocin in the natural initiation of labor has been suspected but not proven, but oxytocin is used clinically to induce or augment labor. Undesirable effects of administered oxytocin, such as fetal hypoxia, are associated with excessively strong uterine contractions or inadequate uterine relaxation between contractions (see also Chapter 2.14).

Vasopressin influences the transamniotic water transfer from the mother to the fetus. Vasopressin is inactivated by vasopressinase. During pregnancy, subclinical diabetes insipidus may be aggravated as a result of increased levels of placental vasopressinase. Vasopressin deficiency results in diabetes insipidus, for which vasopressin or its analogs have been used as therapy. The peripheral anomalies of the extremities that have been induced by vasopressin in animal experiments (Love 1973, Davies 1970, Jost 1951), apparently caused by vasoconstriction, have not, as yet, been observed in human beings. Among the natural and synthetic analogs are argipressin, desmopressin (DDAVP), lypressin, ornipressin, and terlipressin. Desmopressin, which is not inactivated by vasopressinase, has been most frequently described in connection with the treatment of pregnancy-related diabetes insipidus. DDAVP, at therapeutic

2.15.5 Thyroid function and iodine supply during pregnancy maternal drug concentration, does not appear to cross the placenta within detectable limits using an in vitro human placental model (Hay 2004). The available experience from approximately 50 documented cases exposed to desmopressin is not sufficient for a well-grounded assessment of the teratogenic potential of these synthetic hormones (Brewster 2005, Lacassie 2005. Siristatidis 2004, El-Hennawy 2003, Ray 1998).

Because desmopressin can promote the release of clotting factors, this agent has been used in the management of mild hemophilia, von Willebrand's disease type I, and platelet dysfunction, such as after therapy with acetylsalicylic acid (ASS). It is usually administered only briefly peripartum (Castaman 2006, Gojnic 2005, Percz-Barrero 2003).

Recommendation. Oxytocin may be used obstetrically for the induction or augmentation of labor. Clinically important vasopressin deficiency (diabetes insipidus) justifies the use of vasopressin or desmopressin during pregnancy. Careful control of circulatory and kidney function is essential. Von Willebrand's disease type I and platelet dysfunction can also be indications for the administration of desmopressin. The use of the other vasopressin analogs is not grounds for a termination of pregnancy or for Invasive diagnostic procedures.

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