Effects of medicinal products on the composition and secretion of mother's milk 

Dimitar Kehayov1

1Emergency Medical Assistance Centre, town of Burgas 

 In particular, medicinal products may interact with the following processes:

  • Normal development of mammary glands.
  • Secretion of breast milk.
  • Hormonal regulation of mammary glands in the period of lactation.
  • Food supply to cells secreting breast milk in the mammary glands.

The effect of medicinal products on some of these processes has been well researched. As an example in this respect we can point out the role of dopaminergic medicinal products on the secretion of Prolactin, which is main lactogenic hormone.

Effect of medicinal products on normal development of mammary glands

Oestrogens and anti-oestrogens

Oestrogens play an essential role in the development of mammary glands during puberty. Many pieces of evidence exist that the oestrogen replacement therapy in ovarectomied pre-puberty animals helps in the development of ductusies of mammary glands, as well as that the application of the specific oestrogen antagonist ICI 163-438, implanted on mammary glands of mice, inhibits the development of ductusies (research by Sibestrein and others) (1). We can conclude from this experiment that any medicinal product, which hinders the action of oestrogens, has the potential to inhibit the normal development of mammary glands.

Anti-oestrogens may have various effects. The classic manner of impact is their direct interaction with oestrogen receptors, which directly inhibits the effect of oestrogen on oestrogen-sensitive cells (2). Some medicinal products, such as triphenylene anti-oestrogens, may also be associated with membrane associated anti-oestrogen areas (3). Compounds such as 2,3,7,8 -tetrachlorodibenzo-p-digoxin (ТСDD) may stimulate oestrogen degradation (4) by causing disregulation of oestrogen metabolizing enzymes. Other products, such as 6-hydroxymonoandrostenedione, may inhibit the action of aromatase and thus suppress synthesis of oestrogen (5.6). 

Oestrogen antagonists, such as Tamoxifen & ICI 163-438, connect directly with oestrogen receptors, which inhibits competitively the action of oestrogens as a transcriptional regulator. Biswas & Vonderhaar (7,8) indicate that Tamoxifen and triphenylene antiestrogens connect with Prolactin receptors, which inhibits Prolactin's connection of  with them. This interaction seems to be in the basis of the inhibition of prolactin-stimulated synthesis of casein in mammary glands from the application of Tamoxifen. The effect of Tamoxifen and Oestradiol on the development of mammary glands with pre-puberty female pigs has been best researched by Linn & Buttle (9). Tamoxifen, which is fractional oestrogen antagonist, stimulates the development of mammary glands when it is applied individually, but inhibits the effect of oestradiol when both products are given simultaneously.

Another category of compounds have the potential to inhibit the synthesis oestrogen, through interaction with aromatase, which converts androgynous precursors to active oestrogen. Thus Gervias & Tan have identified male steroidal hormone analogue, 6-hydroxyminoandrostenedion, which both impacts simultaneously aromatase and has tumour inhibiting effect on cultures of human T47D neoplastic tumour cells from carcinoma of mammary glands (5). Kadohama and associates established that ingredients of tobacco, acyl-derivatives of nicotine and anabasine, suppress the production of oestrogens in cell cultures of mammary glands (6).

Medicinal products, which may affect hormonal environment, which supports lactation

Prolactin

Prolactin is a hormone, which is needed for secretion of breast milk, and also probably plays a role in the development of mammary glands in women. Secretion of Prolactin from the front part of the pituitary gland is controlled primarily by dopaminergic neurons of the tuberoinfundibular pathway, as well as by cellular elements, localised both in the hypothalamus and periventricular and caudal areas of the central nervous system (10). The secretion of Dopamine by these neurons defounds in the capillary meshes of the pituitary portal system and is transported to the front pituitary gland as well. The activity of these neurons is controlled following the principle of the negative feedback (i.e. the levels of Dopamine exert a regulatory effect on their activity) or by autoreceptors; their activity, however, is inhibited by sucking during lactation and therefore it has been identified that during lactation Prolactin inhibits their activity according to the principle of the negative feedback (10). In the front pituitary gland Dopamine interacts with D2 membrane receptors, localized on Prolactin secreting cells as well. The activation of these receptors by dopaminergic agonists inhibits the secretion of Prolactin, particularly by G-protein dependent inhibition of сАМР (11). Signal transduction may be mediated through the activation of both potassium channels and cell hyperpolarization, but not by direct inhibition of voltage-dependent calcium channels (12).

Pharmacological products affect the secretion of Prolactin by modifying the activity of dopaminergic neurons, by competitive displacement of Dopamine from the places of connection with its receptors or by direct activation of Dopaminergic receptors, located on the Prolactin secreting cells in the front part of the pituitary gland (13). The therapeutically significant medicinal products, which may inhibit the secretion of Prolactin, act through the activation of D2 receptors. Many of these medicinal products are ergot alkaloids. The prototype of these medicinal products is Bromocriptin, which has also been approved for the treatment of hyperprolactinemia, regardless of whether it is associated with the presence of tumours of the pituitary gland or not. Bromocriptine is normally taken twice a day, but for women who cannot tolerate its oral intake it is applied vaginally too, with the same therapeutic effect (14). The analogues of Bromocriptin, which inhibit lactation, include: Dihydroergocristine, Lisuride, Terguride, Pergolide and Cabergoline. The use of Bromocriptine for inhibition of post-partum lactation in the United States is prohibited due to development of cardiovascular complications in the breast feeding woman (15,16).

The use of other dopaminergic agonists, such as Ibopamide, which is a structural analogue of Dopamine, also inhibits lactation (17,18). L-Dopa, which is metabolized to Dopamine in the cerebrum, inhibits abnormal lactation too (19). The use of indirectly acting Dopamine agonists, such as Amphetamine and Nomifensine, is also associated with the reduction of plasma levels of Prolactin in the body of the woman, but clinically lactation is not suppressed (20,21).

Unlike dopaminergic agonists, medicinal products which have an affinity to D2 receptors, but do not have internal activity, may inhibit the effect of endogenous Dopamine and cause development of hyperprolactinemia, both in men and women (22,23). Their effect is shown in some patients with galactorrhea or gynecomastia. D2 receptor antagonists, which are used clinically as neuroleptics, include representatives, which belong to different chemical classes: phenotiazines (Chlorpromazine), butyrophenones (Haloperidol), benzoxazoles (Risperidone), benzamides (Remoxipride), etc. There is a correlation between their potency to suppress productive symptomatics and their ability to induce hyperprolactinemia (13). There is also a correlation between the continued use of neuroleptics and the increased risk of development of breast cancer (24). Atypical neuroleptics, such as  Clozapine, are relatively weak D2 antagonists and practically almost do not antagonize the Dopamine - induced inhibition of the secretion of Prolactin by the pituitary gland in vitro (25), most of them cause a transitory increase of Prolactin levels during the use of standard therapeutic doses (26).

D2 receptor antagonists, which are used as antiemetics or prokinetics, may also lead to the development of hyperprolactinemia. Thus, for example, the application of Metoclopramide in standard therapeutic doses leads to elevation of serum levels of Prolactin (27), mainly of the non-glycolized form of the hormone (28). The use of Metoclopramid during the period of lactation is associated with an increase in the volume of breast milk without any change in the concentration of Prolactin in breast milk (29). Domperidone, another dopaminergic antagonist, which is used for the treatment of motility gastrointestinal diseases, however, increases the levels of the serum Prolactin (30).

The secretion of Prolactin is increased by the application of agonists as well, which activate cholinergic and/or triptaminergic receptors in the central nervous system. There is evidence that these effects are mediated by the effect of the products in the dorsal arcuate nucleus, which reduces the dopaminergic neurotransmission in the tuberoinfundibular pathway (31). Opioid agonists, both alkaloids and peptides, also increase the secretion of Prolactin, through the reduction of the secretion of Dopamine (32). Opioid-induced increase in secretion of Prolactin is particularly expressed during the period of lactation, probably because of the increase in adrenal cortical hormones (33). The role of endogenous opioid peptides for the secretion of Prolactin remains unclear, so much more that the application of the opioid antagonist Naloxon does not influence basal levels of Prolactin or available hyperprolactinemia, caused for various reasons (34). Some studies in animals show that opioids contribute to the increase of Prolactin levels, which develops as a result of sucking. 

Tryptaminergic agonists, which increase the levels of Prolactin, include: Serotonin, Tryptophan (a precursor of Serotonin), Fenfluramin (Serotonin releasing product), Fluoxetine (inhibitor of reverse intake of Serotonin), Moclobemide (МАО-A inhibitor), as well as both the non-selective medicinal product m-chlorphenylpiperazine and selective medicinal products such as Buspirone and 8-hydroxy-2- (di-n-propylamino)tetralin. Serotonin-releasing neurons probably contribute to the secretion of Prolactin in response to sucking (32).

The secretion of Prolactin is also induced by the thyreo-releasing hormone, which affects pituitary cells directly (35,36). The physiological significance this impact, however, still remains unclear. The synthetic form of this tripeptide (thyrotropin-releasing hormone), Proterelin, is available for clinical use and is used for the diagnosis of Prolactin secretion.

Oxytocin

Oxytocin is secreted as a consequence of both sucking and the presence of some physiological stimuli, such as the crying of the newborn. Oxytocin causes contractions of myoepithelial cells, located around alveoli and ductusies, and this has the secretion of breast milk as a consequence. 

Ethyl alcohol is a powerful inhibitor of oxytocin secretion. The chronic intake of ethyl alcohol in experiments with rats during a period of lactation, leads both to the reduction of the volume of the secreted breast milk and to a change in the normal composition of breast milk, levels of lactose in it reduce and its lipid content increases (37).

The powerful effect of opioids on the secretion of Oxytocin was proven by the studies of Haldar and Rayner, which show that the application of morphine inhibits the release of Oxytocin, which develops as a result of the generation of a sucking reflex, which is demonstrated in experiments with rats (38,39). These effects of opioids, however, have not been well-researched in women, who are in a period of lactation. In a single study the application of Naloxon, an opioid antagonist, has no effect on the secretion of Oxytocin, but partially neutralizes the alcohol-induced inhibition, which indicates that the effect of ethanol is realized also by impact by opioid neuron pathways, and also that the secretion of Oxytocin is not a subject to chronic inhibition by opioids during the period of lactation (40).

Prostaglandins

The effect of prostaglandins on the secretion of breast milk was researched yet in the 70s of the last century, but obtained  results were very contradictory (41,42,43).

In modern research it has found that prostaglandin E2 possesses the effectiveness of Bromocriptine in the suppression of postpartum lactation in women (44).

Other hormones 

Studies in animals and tissue cultures show that the application of glucocorticosteroids is necessary for the implementation of the normal lactation, both in vivo and in vitro (45,46). Unfortunately, however, there is no research to determine the effects of chronic glucocorticosteroid therapy on lactation, probably because breastfeeding is not indicative in women, who take this class of medicinal products for a long time, and also because of their potential to accumulate in breast milk.

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