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.

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.

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.].

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.

Estrogen-induced galactorrhea in man.

A 36-year-old man had estrogen-induced galactorrhea and oligospermia. He had been taking an unknown amount of estrogen for a year. While hypogonadism, manifested by decreased libido and potency, was apparent at the time of estrogen administration, galactorrhea appeared two months after estrogen was discontinued. Normal skull film, tomogram views of the sella turcica, and computerized axial tomography scan suggested that long-term estrogen administration caused sustained hyperprolactinemia with levels that ranged between 21 and 83 ng/mL throughout the ensuing year. Prolonged thyroid-stimulating hormone and prolactin luteinizing hormone response to luteinizing hormone-releasing hormone were believed to be evidence of a derangement in the hypothalamic control of pituitary hormone secretion. A year after he stopped taking estrogen, the patient gradually regained his potency, his prolactin level declined, the galactorrhea disappeared, and spermatogenesis returned to normal.

Clinical and endocrinological analyses of patients with galactorrhea and menstrual disorders due to sulpiride or metoclopramide.

The clinical courses of galactorrhea and menstrual disorders were studied in 18 women with galactorrhea induced by sulpiride (SLP) or metoclopramide (MCP) given for the treatment of gastrointestinal diseases. The response of PRL and TSH to 500 micrograms iv TRH and the response of LH and FSH to 100 micrograms LRH were assessed by retrospective analysis during treatment in nine patients (six, SLP; three, MCP) and shortly after the end of treatment in nine patients (seven, SLP; two, MCP). The average time from the initiation of treatment to the onset of galactorrhea was 27.2 +/- 4.7 (mean +/- SE) days in the 13 SLP-treated patients and 23.2 +/- 5.8 days in the 5 MCP-treated patients. Five of the SLP-treated patients experienced amenorrhea, four had oligomenorrhea, and one had dysfunctional bleeding. In the MCP-treated patients, oligomenorrhea and dysfunctional bleeding occurred in one each. The average length of time from the end of treatment to disappearance of galactorrhea was 50.0 +/- 7.3 days in the SLP-treated patients and 56.6 +/- 12.1 days in the MCP-treated patients. Cyclic uterine bleeding returned within 2 months after treatment was stopped. Elevated PRL levels with good response to TRH were observed in four of six patients during SLP treatment, and in two of three patients during MCP treatment. Basal PRL levels and response to TRH were normal in almost all patients after the drugs were withdrawn. Normal HL and FSH levels with exaggerated responses of LH to LRH were observed in most patients during treatment, whereas the response of LH to LRH was normal in about half of the patients after treatment. Our findings suggest that hyperprolactinemia in patients treated with SLP or MCP may be in part the cause of both galactorrhea and menstrual abnormalities, and that these symptoms can be reversed by stopping treatment, provided the patients have not taken the drugs for longer than a year.

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.

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.

Galactorrhea and hyperprolactinemia during treatment of polycystic ovary syndrome.

The serum concentration of prolactin and the presence of galactorrhea were evaluated systematically in a prospective study of the effect of medroxyprogesterone acetate (MPA) in polycystic ovary syndrome (PCO). In 21 patients, the diagnosis of PCO was made by laparoscopy. Three women presented with galactorrhea and increased prolactin levels, 2 had galactorrhea with normal prolactin levels, and 3 had an isolated elevation in the serum concentration of prolactin. Treatment with MPA induced galactorrhea in 10 additional patients. Elevated levels of prolactin were detected in 18 of the patients during treatment. There was no correlation between the score for galactorrhea and the level of prolactin. Tomograms of the sella turcica were abnormal in 3 of 8 patients with hyperprolactinemia. The authors conclude that galactorrhea and/or hyperprolactinemia are important side effects of MPA in patients with PCO.

Neuroendocrine dysfunction in galactorrhea-amenorrhea after oral contraceptive use.

Nonpuerperal alactorrhea and amenorrhea have been reported following the use of oral contraceptives. Treatment of this condition with ergot alkaloids has proved to be of great therapeutic value. Pretreatment plasma hLH and hFSH concentrations in 13 women with postqill galactorrhea-amenorrhea (PPGA) were 6.6 plus or minus 0.6 (SE.) and 5.0 plus or minus 0.8 mlU/ml, respectively. The mean prolactin concentration was 80.7 plus or minus 13.2 ng/ml. After complete evaluation in which diagnostic evidence of pituitary tumor was absent, the patients were treated with ergocryptine (CB-154). The mean hPRL concentration at 14 days of therapy was 7.8 p;us or minus 1.9 ng/ml. Cyclic gonadotropin secretion resumed in all but one instance; ovulation was confirmed on the basis of a biphasic temperature chart and in 5 cases, endometrial biopsy. Measurement of serum dopamine-beta-hydroxylase (DBH) activity indicated a significant decline at the end of 8 weeks of CB-154 therapy. The fall in hPRL was not necessarily associated with a fall in DBH. The majority of women in this study exhibited a consistent personality suggesting varying degrees of anxiety unrelated to the PPGA and usually antedating the use of oral contraceptives. PPGA was found in women without hyperprolactinemia, but altered hPRL secretion was evident in all instances. The data suggest that the disorder of cyclic gonadotropin secretion is related to altered hPRL secretion, but the mechanism is possibly related to a catecholamine abnormality. The data support the presence of an inherent cyclic mechanism for the secretion of gonadotropins. CB-154 therapy does not affect conception, and no teratogenic effects were observed in 2 infants born to women who had received CB-154 during the first 40 days of gestation.

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.

Prolonged over-suppression syndrome.

PIP: The syndrome of postpill amenorrhea was investigated retrospectively by studying records of diagnosed cases of amenorrhea (1300) treated or confirmed at the Mayo Clinic. Data are taken from records dating to 1960 (low use of contraceptives) and terminate in 1971. 12 cases are reviewed which were diagnosed as prolonged oversuppression syndrome. No particular oral contraceptive formulation was implicated. 4 of 12 patients had had irregular menstrual cycles before oral contraceptive therapy; whereas 8 had had regular cycles. Bioassay of urinary gonadotropins were consistently in the mid-low normal limits (only 1 determination was available for each patient); some patients had been radioimmunoassayed (single assay) for other pituitary hormones: LH (luteinizing hormone) was at normal basal levels and FSH (follicle stimulating hormone) was also in the normal range. Concentrations of total circulating estrogens were in low or subnormal range in each case. 4 cases had associated galactorrhea, which was attributed to exogenous steroid suppression of the prolactin-inhibiting center of the pituitary. Clomiphene citrate was used to restore functions of the hypothalamic-pituitary axis, and of the 8 receiving clomiphene, 5 responded and 2 conceived.^ieng

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.

Adverse reactions to antihypertensive drugs in pregnancy.

In conclusion from a clinical pharmacological point of view it is stressed that side effects from antihypertensive therapy in part is related to dosage. Increased knowledge should make it possible to reduce the rate of side effects. In the individual case the physician always has to compare a number of factors: general condition of the patient, age, adherence to the prescribed therapy, side effects, and other factors in addition to blood pressure values. With all these limitations in mind there is agreement that the benefit of antihypertensive therapy far out-weigh the negative aspects of such treatment.

A neglected Mayan galactagogue - ixbut (Euphorbia lancifolia).

A herbal tea, made of leaves of ixbut (Euphorbia lancifolia Schlecht.), has been used for several centuries by postpartum Mayan women in Guatemala to stimulate and increase the flow of mother's milk. Ixbut, when mixed with cattle fodder, is reputed to have increased milk yields in cows. To date, the active principle of ixbut has never been isolated. However, this medicinal herb, a natural galactagogue of Central American origin, would appear to be worthy of further chemical and pharmacological study. The following illustrated article describes the history and use of ixbut, and includes chromatographic analyses of dried ixbut leaves from Guatemala.

Galactorrhea in oral contraceptive users.

One hundred women who had been employing combination estrogen/progestin oral contraceptives (OCs) for a minimum of six consecutive months were evaluated for the presence of galactorrhea. It was found in 9%. The incidence did not vary significantly with age, gravidity, duration of OC use of estrogen content. Only six subjects had breast fed previously, preventing assessment of the effect this may have on the incidence of galactorrhea. Twelve OC users with galactorrhea were evaluated for the presence of pituitary microadenomas. Two had radiologic and hormonal findings consistent with the presence of prolactinomas, one had functional hyperprolactinemia, one had an empty sella, one had a partially empty sella, and two with normal basal prolactin levels had both polytomography and computerized axial tomography findings suggestive of pituitary microadenomas. Galactorrhea in OC users who have not breast fed is frequently associated with significant intrasellar pathology and should be an indication for further evaluation.

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.

Hyperprolactinaemia and nonpuerperal lactation associated with clomipramine.

Clomipramine in therapeutic dose was associated with nonpuerperal lactation and an elevated plasma prolactin. Both features resolved within weeks of discontinuing the drug.