Biological effects of anti-RANKL antibody administration in pregnant mice and their newborns.

Denosumab, a fully human monoclonal antibody that neutralizes receptor activator of nuclear factor-κB ligand (RANKL) and blocks osteoclast differentiation, has received approval in Japan for use as an anti-resorptive drug for osteoporosis and skeletal-related events (SREs) in patients with solid cancer. Denosumab is contraindicated during pregnancy, though the effects of blocking RANKL activity on pregnant mothers and their newborns are unclear. We used mice to investigate the effects of an anti-RANKL antibody on maternal and newborn health. Mothers injected with the anti-RANKL antibody had increased bone mass as compared with the controls, while osteoclast number and the level of tartrate-resistant acid phosphatase (TRAP) in serum were increased at the end of pregnancy. Newborn mice exposed to the antibody in utero were normally born, but showed increased bone mass and died within 48 h after birth. None of the newborns were found to have milk in their stomachs, suggesting that they died due to a maternal defect in lactation. Consistent with this, anti-RANKL antibody-injected mothers displayed impaired mammary gland development. However, fostering by healthy surrogate mothers rescued only 33% of the antibody-exposed newborns, suggesting that neonatal mortality was due, at least in part, to an intrinsic defect in the newborns. Our findings show that anti-RANKL antibody administration during pregnancy results in not only an undesirable increase in bone mass, but also has harmful effects on newborn survival.

Corticosteroid Injections: A Review of Sex-Related Side Effects.

Corticosteroid injections are used as a nonoperative modality to combat acute inflammation when conservative treatments fail. As female patients are regularly seen by orthopedic physicians, it is essential to identify and understand potential sex-related side effects. The aim of this article is to examine available literature for sex-related side effects of orthopedic-related corticosteroid injections. Although the incidence is low, sex-related side effects, such as abnormal menstruation, lactation disturbances, facial flushing, and hirsutism, are associated with corticosteroid injections. Physicians should be aware of these female-specific side effects and relay this information as part of the informed consent process. [Orthopedics. 2017; 40(2):e211-e215.].

Sudden loss of milk supply following high-dose triamcinolone (Kenacort) injection.

Endogenous corticosteroids are involved in breast development, initiation and maintenance of milk production. Animal studies have shown that exogenous corticosteroids diminish milk production and milk ejection. A high dose depot injection of triamcinolone resulted in dramatic reduction in milk production in an established lactation. Domperidone and frequent expression restored milk production. Lower dose depot injection of betamethasone into the shoulder joint did not noticeably reduce milk production.

[Effects of Maidang Rutong granule on l-dopa-induced galactozemia in rats].

OBJECTIVE: To study galactagogue effect of Maidang Rutong granule on the lactation rats. METHOD: The experiments were designed to observe the efficiency of Maidang Rutong granule on lactescence, serum prolactin, and morphology of mammary gland with rat galactozemia model established by injecting l-dopa. RESULT: Maidang Rutong granule showed significant enhancement for lactescence and the offspring's body weight. It could antagonize the decrease of serum prolactin and the atrophy of mammary gland induced by l-dopa. CONCLUSION: Maidang Rutong granule exhibited significant galactagogue effect on the l-dopa-induced galactozemia in rats.

Does continuing oral magnesium supplementation until delivery affect labor and puerperium outcome?

OBJECTIVE: To determine the labor and puerperal impact of continuing oral magnesium supplementation until delivery. STUDY DESIGN: Single-center study with matched controls. In 40 pairs of healthy women with vaginally delivered singleton pregnancies, matched for maternal age, race and parity, maternal and neonatal outcome endpoints were compared in those receiving continuous oral magnesium aspartate supplementation 15-30 mmol/d for at least 4 weeks until delivery (for constipation, calf cramps, preterm contraction without cervical effacement or additional tocolytics) versus non-supplemented controls. RESULTS: In the magnesium group labor was nonsignificantly longer (stage 1: 326.0+/-187.5 min versus 276.7+/-140.8 min, P = 0.19; stage 2: 52.0+/-44.5 min versus 43.5+/-44.0 min, P = 0.40) and maximum oxytocin dose nonsignificantly higher (14.5+/-9.4 [median 12.0; n=15] versus 10.5+/-6.9 [median 7.5] mU/min, P = 0.28; n = 10). Fewer women had afterpains (12 versus 20, P=0.11), required spasmolysis (3 versus 14, P = 0.005), or could breastfeed their infants exclusively at discharge (24 versus 34, P = 0.04). CONCLUSION: Continuing oral magnesium supplementation until delivery does not significantly prolong labor or increase the oxytocin requirement, but it significantly impairs breastfeeding competence.

Use of measures of disproportionality in pharmacovigilance: three Dutch examples.

Spontaneous reporting systems for suspected adverse drug reactions (ADRs) remain a cornerstone of pharmacovigilance. In The Netherlands 'the Netherlands Pharmacovigilance Foundation Lareb' maintains such a system. A primary aim in pharmacovigilance is the timely detection of either new ADRs or a change of the frequency of ADRs that are already known to be associated with the drugs involved, i.e. signal detection. Adequate signal detection solely based on the human intellect (case by case analysis or qualitative signal detection) is becoming time consuming given the increasingly large number of data, as well as less effective, especially in more complex associations such as drug-drug interactions, syndromes and when various covariates are involved. In quantitative signal detection measures that express the extent in which combinations of drug(s) and clinical event(s) are disproportionately present in the database of reported suspected ADRs are used to reveal associations of interest. Although the rationale and the methodology of the various quantitative approaches differ, they all share the characteristic that they express to what extent the number of observed cases differs from the number of expected cases. In this paper three Dutch examples are described in which a measure of disproportionality is used in quantitative signal detection in pharmacovigilance: (i) the association between antidepressant drugs and the occurrence of non-puerpural lactation as an example of an association between a single drug and a single event; (ii) the onset or worsening of congestive heart failure associated with the combined use of nonsteroidal anti-inflammatory drugs and diuretics as an example of an association between two drugs and a single event (drug-drug interaction); and the (iii) (co)-occurrence of fever, urticaria and arthralgia and the use of terbinafine as an example of an association between a single drug and multiple events (syndrome). We conclude that the use of quantitative measures in addition to qualitative analysis is a step forward in signal detection in pharmacovigilance. More research is necessary into the performance of these approaches, especially its predictive value, its robustness as well as into further extensions of the methodology.

A comprehensive approach to evaluating nipple discharge.

While emphasis is justifiably placed on the importance of detecting breast masses during breast examination, the equally important need for accurate assessment of nipple discharge is often overlooked. Inspection and palpation for nipple discharge should be part of every breast examination. When detected, a critical analysis should be made of every nipple discharge, with the ultimate objective being differentiation between benign and malignant discharges. All nipple discharges can be defined by the physical characteristics of laterality, spontaneity, color, consistency, number of ducts involved, and duration. By correlating these characteristics with certain historical features (e.g., age, pregnancy, trauma, drugs), accurate determination of etiology can be made. A four-step approach is presented that offers a logical method for making the essential correlations. The sequence of the four relevant questions proposed gives the examiner a logical basis from which to assign clinical importance to each discharge. An algorithm is outlined that correlates diagnostic considerations with therapeutic actions.

Black breast milk due to minocycline therapy.

We report the unusual case of a 29-year-old female who developed black discoloration of breast milk 3 weeks after commencing oral minocycline therapy for acne vulgaris. Histochemical analysis of the breast milk revealed the presence of pigment particles within macrophages with iron staining characteristics. We propose that the pigment may represent an iron chelate of minocycline or one of its derivatives.

Usefulness of recombinant human prolactin for treatment of poor puerperal lactation in a rat model.

Recombinant human prolactin (r-hPRL) was produced by a line of murine C127 cells transfected with human PRL gene. To assess the biological efficacy of r-hPRL in vivo, we studied its influence on milk secretion using a rat model in which lactation was reduced by bromocriptine treatment. Puerperal rats were injected daily for 9 days after delivery with bromocriptine or bromocriptine plus r-hPRL, and lactational performance was assessed by weighing the pups. The concentrations of rat and human PRL in rat serum were measured by specific radioimmunoassays and the mammary glands were examined on postpartum day 10. Daily injection of bromocriptine (0.1 mg/rat) significantly reduced the endogenous level of rat PRL and impaired the weight gain of the pups. Administration of r-hPRL increased the serum level of human PRL. Daily injections of r-hPRL (50 micrograms/rat, twice a day) restored lactational performance and significantly increased the weight of the pups. The detrimental effect of bromocriptine on the mammary glands, assessed by both weight and histological appearance, was reversed by administration of r-hPRL. These results demonstrate that r-hPRL is biologically active in vivo and replacement therapy of r-hPRL is effective in improving the lactational performance in bromocriptine-treated rats, and also that r-hPRL may be useful for the treatment of women with poor lactation.

Can magnesium sulfate therapy impact lactogenesis?

This case report describes a patient who ingested magnesium sulfate (MgSO4) for approximately four days as a treatment for pregnancy-induced hypertension. Stage II lactogenesis was delayed until the tenth postpartum day at which point the patient's breasts became fully engorged. No explanation for this delay was found, other than the possibility that magnesium sulfate treatment impeded lactogenesis. Implications for professionals who care for lactating women are discussed.

Cimetidine-induced galactorrhea.

Various breast abnormalities have been described in patients treated chronically with cimetidine, but galactorrhea has been reported only twice in the medical literature. In both cases, there appeared to be an associated hyperprolactinemia. These problems could well represent a consequence of histamine2-receptor blockade. We report here a female patient with hepatic cirrhosis and portal hypertension who developed hyperprolactinemia and galactorrhea while on long-term cimetidine therapy. Both the hyperprolactinemia and the galactorrhea disappeared when the patient was switched to ranitidine, an alternative H2-receptor blocker. A review of the previous case reports and relevant literature is included.

Serial plasma prolactin levels in neuroleptic-induced galactorrhea: a case report.

A patient was successfully treated with bromocriptine for neuroleptic-induced galactorrhea. The correlations of the weekly plasma prolactin levels with the severity of galactorrhea (p less than .005) and with the duration of treatment (p less than .001) were highly significant. Because symptomatic relief occurs an average of 6 to 8 weeks after initiation of pharmacotherapy, clinicians presently manage neuroleptic-induced galactorrhea by trial and error. The authors suggest that weekly plasma prolactin levels may provide a readily obtainable, early indicator of proper dosage and thus minimize the chance of iatrogenic illness.

Antidepressants and galactorrhoea.

Several antidepressants have been reported to produce hyperprolactinaemia, with or without galactorrhoea. We report a case of galactorrhoea associated with dothiepin and discuss the effects of a subsequent change in antidepressants.