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Association of gestational diabetes with other lactation-related disorders: A 2-sample Mendelian randomization analysis of causal effects.

Gestational diabetes mellitus (GDM) is associated with adverse metabolic outcomes and may also be related to postpartum breast and lactation disorders. Observational studies are susceptible to confounding and reverse causation. We used a 2-sample Mendelian randomization design to examine the association between genetic liability to GDM and other disorders of the breast and lactation associated with childbirth. Genetic liability to GDM was associated with higher odds of a composite phenotype of breast and lactation disorders associated with childbirth. Replication using independent samples and more specific clinical outcomes is required. Summary statistics for GDM and the FinnGen outcome "other disorders of breast and lactation associated with childbirth" were obtained from the Integrative Epidemiology Unit open genome-wide association study resource. single nucleotide polymorphisms associated with GDM (P&#x2005;<&#x2005;5&#x2009;&#xd7;&#x2009;10-6) were clumped (R2&#x2005;<&#x2005;0.001) within 10,000&#x2009;kb. The inverse-variance weighted method was the primary analysis; Mendelian randomization-Egger, weighted median, simple mode, and weighted mode analyses were complementary methods. Heterogeneity, directional horizontal pleiotropy, leave-one-out, and Steiger directionality analyses were performed. Nineteen single nucleotide polymorphisms were retained; F statistics ranged from 21.08 to 288.04. Genetic liability to GDM was associated with higher odds of the outcome in the inverse-variance weighted analysis (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.08-2.09; P&#x2005;=&#x2005;.0165). The weighted median (OR, 1.76; 95% CI, 1.09-2.84; P&#x2005;=&#x2005;.0216) and weighted mode estimates (OR, 1.98; 95% CI, 1.21-3.26; P&#x2005;=&#x2005;.0148) were directionally consistent. There was no statistical evidence of heterogeneity or directional horizontal pleiotropy. The Steiger test supported the direction from GDM to the outcome (P&#x2005;=&#x2005;1.30&#x2005;&#xd7;&#x2005;10-11).

Diabetes, Gestational

Dynamic allelic expression in mouse mammary glands across the adult developmental cycle.

The mammary gland, which primarily develops postnatally, undergoes significant changes during pregnancy and lactation to facilitate milk production. Through the generation and analysis of 480 transcriptomes, we provide the most detailed allelic expression map of the mammary gland, cataloguing cell-type-specific expression from ex-vivo&#xa0;purified cell populations over 10 developmental stages, enabling comparative analysis. The work identifies genes involved in the mammary gland cycle, parental-origin-specific and genetic background-specific expression at cellular and temporal resolution, genes associated with human lactation disorders and breast cancer. Genomic imprinting, a mechanism regulating gene expression based on parental origin, is crucial for controlling gene dosage and stem cell potential throughout development. The analysis identified 25 imprinted genes monoallelically expressed in the mammary gland, with several showing allele-specific expression in distinct cell types. No novel imprinted genes were identified and the absence of biallelically expressed imprinted genes suggests that, unlike in brain, selective absence of imprinting does not regulate gene dosage in the mammary gland. This research highlights transcriptional dynamics within mammary gland cells and identifies novel candidate genes potentially significant in the tissue during pregnancy and lactation. Overall, this comprehensive atlas represents a valuable resource for future studies on expression and transcriptional dynamics in mammary cells.

Animals

On the agalactia post partum in the sow. A clinical study.

The purpose of the present investigation was to study the clinical symptoms of agalactic sows post partum in randomly selected swine herds. The study comprised 71 sows affected with agalactia post partum and 71 healthy sows from the same herds used as controls. Average morbidity of the disease in these 50 herds, consisting of an average of 25 sows, was 12.8%. Sixty-three per cent of the agalactic sows were affected within one day after farrowing. There was no difference in gestation length between healthy sows and agalactic sows. The body temperature was significantly higher for affected than for healthy sows. Mastitis was diagnosed in 35 out of 71 agalactic sows. The criteria for mastitis were swelling and herdening of one or several udder glands. Vaginal discharge was recorded for affected sows (55/57) as well as for healthy sows (51/58) and is therefore not significantly associated with agalactia. The temperament of the agalactic sows was moderately or severely affected in 62 out of 71 agalactic sows. Constipation was recorded for 13/59 agalactic sows and for 3/57 normal sows. The agalactic sows had significantly higher number of piglets per litter at birth while the litter size was higher for healthy sows at weaning. Numerically, more sows were culled among agalactic sows (16/48) than among normal sows (6/42). Moreover, sows affected with agalactia at the previous parturition were more inclined to meet with the disease at the next parturition. Further studies comprising large groups of animals are, however, necessary for evaluation of this question.

Animals

Plasma prolactin-releasing factor-like activity in the amenorrhea-galactorrhea syndrome.

An in vitro bioassay for plasma PRL-releasing factor-like activity has been developed. The method is a three-phase methanol extraction of plasma with extracts of 1.0 ml plasma adjusted to a final volume of 50 microliter. Single 50-microliter aliquots of extract were incubated in 1.0 ml Krebs-Ringer phosphate (KRP) buffer with one rat hemipituitary after a 1-h preincubation. Samples were obtained basally and 30 min after addition of the extract. During each set of incubations, a parallel series of hemipituitaries was incubated in KRP alone. The total nanograms of rat PRL released per mg pituitary tissue during the initial 30 min after preincubation was calculated for all studies. The mean quantity released in KRP alone was considered basal and was subtracted from values obtained during incubation with plasma extracts. The quantity remaining was considered PRL-releasing activity (PRA) of plasma, expressed as nanograms of rat PRL released per mg pituitary. The PRA in plasma from 13 patients with the amenorrhea-galactorrhea syndrome was 132 +/- 17 ng/mg pituitary (X +/- SE), which was significantly greater (P less than 0.001) than the PRA in plasma from eight matched controls [31 +/- 10 ng/mg pituitary (X +/- SE)]. The patients' individual PRL levels were elevated (range, 48-248 ng/ml), and when compared to the PRA in the samples, a highly significant (P less than 0.001) positive correlation evolved. These results indicate that a circulating PRL-releasing factor-like material present in normal plasma is higher in plasma from hyperprolactinemic patients in direct relationship to the PRL concentration. It is possible that this material is related to the pathogenesis of PRL-secreting pituitary disorders.

Adult

Detection, evaluation, and treatment of pituitary microadenomas in patients with galactorrhea and amenorrhea.

Over a period of two and a half years, 34 women with galactorrhea or amenorrhea, all with an abnormal sellar polytomogram, underwent transsphenoidal microsurgical exploration of the sella. Eighteen women and microadenomas (less than or equal to 1 cm. in diameter), seven had macroadenomas (greater than than 1 cm. in diameter), and five had unidentified lesions. Only one women had a normal pituitary gland. Three women had cryosurgery without biopsy. Preoperatively, hyperprolactinemia occurred in 24 of 25 women with adenomas and two of five with nonadenomatous lesions. There were no operative deaths. Significant morbidity occurred in only three patients, none of whom had microadenomas. Postoperatively, menses resumed in 16 of the 17 women with microadenomas and in two of the seven with macroadenomas who presented with amenorrhea. Galactorrhea disappeared in 15 of the 17 women with microadenomas and in four of the seven with macroadenomas who presented with galactorrhea. In five patients with unidentified lesions, a return of menses occurred in two of four with previous amenorrhea, and galactorrhea abated in two of three who presented with lactation. We conclude that sellar polytomography in women with hyperprolactinemia is a useful technique technique for the diagnosis of pituitary adenomas, a lesion which may occur more frequently than previously realized. In addition, transsphenoidal microresection of microadenomas is safe and effective.

Adenoma

Treatment of amenorrhoea, galactorrhoea and hypogonadism with bromocriptine.

The effect of bromocriptine administration was studied in 34 patients, whose presenting symptoms included amenorrhoea, galactorrhoea, infertility, dyspareunia, delayed puberty, and impotence. Two patients were found to have raised plasma prolactin values during investigation for acromegaly. With the exception of three individuals all patients had hyperprolactinaemia. Pituitary fossa enlargement or asymmetry was reported in 16 patients and one patient had primary hypothyroidism. Virtually all patients complained of side effects when first starting bromocriptine but only two patients were unable to tolerate prolonged therapy with doses which ranged from 5--40 mg daily. A single oral dose of 2.5 mg resulted in a greater than 50% reduction in plasma prolactin within five hours in 22 of 26 patients. Over the course of one month, five patients with significant pituitary fossa enlargement appeared to show less rapid suppression of plasma prolactin than five patients without fossa enlargement. At two months this trend was still evident but eventually all patients showed acceptable control of plasma prolactin, with the exception of one patient who required pituitary surgery. Galactorrhoea ceased in 13 of 15 patients, menstrual periods resumed in ten of 13 patients, two patients becoming pregnant first. Potency returned and puberty proceeded in two hypogonadal males. Six of the nine patients requesting treatment for infertility became pregnant. It is concluded that bromocriptine provides effective treatment for galactorrhoea, amenorrhoea or gonadal disorders when there is associated hyperprolactinaemia.

Adolescent

The effect of metoclopramide, TRH and L-dopa on prolactin secretion in pituitary adenoma and in "functional" galactorrhoea syndrome.

The degree of autonomy in prolactin secreting pituitary adenomas and also prolactin secretory reserve in cases with suspected functional galactorrhea syndrome was evaluated with the use of metoclopramide, TRH and L-DOPA. It was found that in patients with pituitary adenoma the basal prolactin (PRL) level often exceeded 150 micrograms/l and the response to stimulation with TRH and/or metoclopramide was markedly diminished or even nonexistent, while the response to L-DOPA was usually retained. In patients with galactorrhoea and/or amenorrhoea, with normal skull X-ray the basal PRL level was either normal or moderately raised but the response to stimulation was various; mostly it was excessive, it was sometimes normal, but in some other cases it was markedly diminished as in patients with adenoma. In the author's opinion the so-called "functional disorder" of prolactin secretion is mainly hyperresponsiveness to stimulation, whereas the basal PRL level in those cases is usually normal or only intermittently raised. In the cases with a moderate hyperprolactinaemia, especially if it appears to be constant, and the response to stimulation is diminished or none at all, we suspect a pituitary microadenoma. Finally, there are rare cases of galactorrhoea with normal basal PRL and normal response to stimulation, in which the sensitivity of the mammary PRL receptor is probably increased. We suggest therefore that the above mentioned PRL stimulation tests may help in distinguishing between tumoural and functional hyperprolactinaemia.

Acromegaly

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.

Adult

Galactorrhea and the defective luteal phase of the menstrual cycle.

Twelve patients with primary infertility due to a defective luteal phase associated with hyperprolactinemia and galactorrhea are reported. All were treated with 2-bromoergocryptine. During the first cycle of therapy, the serum prolactin level decreased in all cases, and galactorrhea disappeared during the second cycle of therapy. Seven women responded to 2-bromoergocryptine, as was reflected in their endometrial biopsies. The remaining five were given clomiphene citrate on the second and sixth days of the next 2-bromoergocryptine cycle. Three of these patients responded favorably to this combined therapy. Six pregnancies were reported during therapy. The results of follow-up after labor or abortion suggested that these cases represent a latent stage of the amenorrhea-galactorrhea syndrome.

Adult

Primary hypothyroidism and galactorrhea.

Ten of 16 women with primary hypothyroidism and high thyrotropin (TSH) concentrations had high serum prolactin (PRL) concentrations. A positive correlation was observed between the basal TSH and PRL levels in the hypothyroid patients. Five of these patients complained of persistent galactorrhea after delivery. After treatment with triiodothyronine (T3), the elevated TSH and PRL levels fell to within normal ranges, and the galactorrhea disappeared. It is suggested that the elevated serum PRL levels of patients with primary hypothyroidism are mediated by feedback-induced thyrotropin-releasing hormone (TRH) secretion or an enhanced response to endogenous TRH, and that the combination of delivery and the PRL excess may induce persistent galactorrhea in patients with primary hypothyroidism.

Adult

Nonpuerperal galactorrhea and hyperprolactinemia. Clinical findings, endocrine features and therapeutic responses in 56 cases.

The clinical and endocrine features, and the responses to different treatment modalities, were examined in 56 patients with galactorrhea and/or hyperprolactinemia after a two month to six year follow-up period. A pituitary adenoma was diagnosed in 17 patients. A prolactin-cell adenoma was identified histologically in eight patients. Other etiologic factors were myxedema (two patients), phenothiazine ingestion (six patients) and breast manipulation (four patients). In 27 patients, including three with abnormalities of the sella turcica, no causal factor was found, and their condition was labelled as dysfunctional in origin. Symptoms were preceded by childbirth in 11 patients and by estrogen-progestin contraception in 22; pituitary adenomas were discovered in both groups in approximately the same frequency (30%) as in the over-all study group. Aside from roentgenographic studies, as well as visual field perimetry in a few cases, a serum prolactin level above 100 ng/ml was the only indicator of a pituitary prolactin-cell adenoma. Prolactin-suppression tests (L-DOPA and 2alpha-Br-ergocryptine) were found to be of no value in discriminating between tumoral and dysfunctional conditions. No significant alterations in prolactin levels occurred after water loading irrespective of basal levels or the nature of the pathologic process. Selective pituitary tumor excision (eight patients) was followed by rapid normalization of prolactin levels and disappearance of clinical abnormalities. Conversely, after pituitary irradiation (eight patients), improvement tended to be slower. Treatment of infertility in those patients without an apparent organic lesion was more successful with 2alpha-Br-ergocryptine (three of three) than with clomiphene (two of seven). Pregnancies following the administration of drugs or after surgical treatment were uneventful. Since follow-up resulted in the early diagnosis of pituitary tumors from seven to 56 months after initial investigation, and since no diagnostic tools are currently available which help to discriminate between tumoral and dysfunctional conditions before abnormalities become evident on roentgenograms, prolonged observation of these patients remains essential.

Adenoma

Effects of alpha- and beta-adrenergic blocking agents on serum prolactin levels in women with hyperprolactinemia and galactorrhea.

The effects of alpha- and beta-adrenergic blocking agents on the serum prolactin levels of six women with hyperprolactinemia and galactorrhea were investigated. There was no indication that pituitary adenomas were etiologic agents for the hyperprolactinemia. Serum prolactin could be lowered with oral L-dopa. When intravenous phentolamine (an alpha-adrenergic blocking agent) or intravenous propranolol (a beta-adrenergic blocking agent) were administered for 1 hour, there was no significant change in serum prolactin levels.

Adenoma

Galactorrhea and pituitary tumors in postpill and non-postpill secondary amenorrhea.

One hundred sixty-seven women with secondary amenorrhea were observed from six months to four years. In 66 patients, the amenorrhea followed the discontinuation of oral contraceptives (postpill) while in the remaining 101 the amenorrhea was not temporally pill related (non-postpill). Galactorrhea was present in 43 (65%) of those with postpill amenorrhea and in 32 (32%) of those with non-postpill amenorrhea (p less than 0.001). Tomography of the sella turcica was performed in the 75 women with galactorrhea and in the 35 without galactorrhea who did not have withdrawal uterine bleeding following progesterone administration and who had low or normal serum follicle-stimulating hormone levels (hypothalamic-pituitary failure). Forty of the 75 patients with amenorrhea and galactorrhea had radiographic evidence of a pituitary tumor whereas only eight of 35 patients with hypothalamic-pituitary failure without galactorrhea had an abnormal sella turcica (p less than 0.01). The incidence of radiographic abnormalities in those with galactorrhea was similar in both the postpill and non-postpill groups.

Adolescent