Galaktocele lub laktoreja – Patofizjologia i mechanizm

Galaktocele lub laktoreja
Patofizjologia i mechanizm

Galaktocele, definiowane jako wydzielanie mleka z gruczołów sutkowych niezwiązane z ciążą lub laktacją, są najczęściej spowodowane hiperprolaktynemią, czyli podwyższonym poziomem prolaktyny w surowicy. Prolaktyna, produkowana przez komórki laktotrofy przedniego płata przysadki mózgowej, reguluje syntezę i wydzielanie mleka, a jej fizjologiczne stężenia u kobiet niebędących w ciąży mieszczą się w zakresie 1-20 ng/ml. Hiperprolaktynemia może wynikać z różnych przyczyn, w tym z prolaktinoma (gruczolaka przysadki wydzielającego prolaktynę), niedoczynności tarczycy, stosowania leków (np. neuroleptyków, SSRI, metoklopramidu), a także z zaburzeń neuroendokrynnych wpływających na hamowanie dopaminergiczne. Wysokie stężenia prolaktyny (>200 ng/ml) korelują z wielkością guza przysadki, a mechanizmy patogenetyczne obejmują zarówno bezpośrednią stymulację komórek nabłonkowych gruczołów sutkowych, jak i hamowanie osi podwzgórze-przysadka-gonady, co prowadzi do zaburzeń owulacji, hipogonadyzmu i niepłodności.

Patofizjologia galaktocele (laktoreji)

Galaktocele (laktoreja) to wydzielanie mleka z gruczołów sutkowych niezwiązane z ciążą lub karmieniem piersią. Za stan ten uznaje się również produkcję mleka pojawiającą się rok po zakończeniu karmienia piersią. Wydzielanie mleka jest procesem fizjologicznym regulowanym przez złożony mechanizm hormonalny, którego głównym elementem jest prolaktyna ¹².

Rola prolaktyny w patogenezie galaktocele

Prolaktyna jest głównym hormonem odpowiedzialnym za syntezę i wydzielanie mleka. Jest wytwarzana przez komórki laktotrofy w przednim płacie przysadki mózgowej. W warunkach fizjologicznych, u kobiet niebędących w ciąży, poziom prolaktyny w surowicy wynosi od 1 do 20 ng/ml (1 do 20 μg/l), w zależności od laboratorium. Podczas ciąży poziom ten może wzrosnąć nawet do 300 ng/ml (300 μg/l) ³⁴.

Wydzielanie prolaktyny podlega rytmowi dobowemu, osiągając najwyższe wartości podczas snu. W regulacji wydzielania prolaktyny uczestniczą dwa główne mechanizmy: hamujący i stymulujący ⁵:

Mechanizm hamujący – głównym czynnikiem hamującym wydzielanie prolaktyny jest dopamina wydzielana z podwzgórza. Dopamina działa poprzez receptory D2 zlokalizowane na komórkach laktotrofów ⁶⁷.
Mechanizm stymulujący – wydzielanie prolaktyny może być stymulowane przez hormon uwalniający tyreotropinę (TRH), wazoaktywny peptyd jelitowy (VIP), a także przez epidermalny czynnik wzrostu ²⁸.

Wzrost poziomu prolaktyny (hiperprolaktynemia) stanowi główną przyczynę galaktocele. Nadmierne wydzielanie prolaktyny prowadzi do nieprawidłowej stymulacji gruczołów sutkowych, powodując wytwarzanie mleka u osób niebędących w ciąży lub niekarmiących piersią ⁹.

Mechanizm serotonergiczny w regulacji wydzielania prolaktyny

Oprócz dopaminy, w regulacji wydzielania prolaktyny uczestniczą także inne neuroprzekaźniki, w tym serotonina. Serotonina może stymulować wydzielanie prolaktyny bezpośrednio poprzez receptory 5-HT w podwzgórzu lub pośrednio poprzez hamowanie wydzielania dopaminy w układzie podwzgórzowo-przysadkowym ¹⁰.

Badania wskazują, że serotonina może stymulować wydzielanie prolaktyny poprzez:

Bezpośrednią aktywację postsynaptycznych receptorów 5-HT w podwzgórzu ¹¹
Pośrednie hamowanie neuronów dopaminergicznych szlaku guzowo-lejkowego ¹²
Stymulację wydzielania wazoaktywnego peptydu jelitowego (VIP) i oksytocyny ¹²

Ten mechanizm wyjaśnia, dlaczego niektóre leki zwiększające poziom serotoniny, takie jak selektywne inhibitory wychwytu zwrotnego serotoniny (SSRI), mogą powodować galaktocele jako działanie niepożądane ¹³.

Przyczyny hiperprolaktynemii prowadzącej do galaktocele

Przyczyny podwzgórzowo-przysadkowe

Najczęstszą przyczyną hiperprolaktynemii związaną z układem podwzgórzowo-przysadkowym są gruczolaki przysadki wydzielające prolaktynę, zwane prolaktinoma ¹⁴.

Prolaktinoma to łagodny guz przysadki wywodzący się z komórek laktotrofowych przedniego płata przysadki. Guzy te podzielone są na dwie grupy ¹⁵¹⁶:

Mikrogruczolaki – o średnicy poniżej 10 mm, częściej występujące u kobiet przed menopauzą
Makrogruczolaki – o średnicy 10 mm lub większej, częściej występujące u mężczyzn i kobiet po menopauzie

Prolaktinoma wywołuje hiperprolaktynemię poprzez nadmierne wydzielanie prolaktyny przez komórki guza. Poziom prolaktyny w surowicy zwykle koreluje z wielkością guza ¹⁷.

Inne guzy przysadki, które same nie wydzielają prolaktyny, również mogą powodować hiperprolaktynemię poprzez ¹⁸:

Ucisk szypuły przysadki, co przerywa dopływ dopaminy z podwzgórza do przysadki
Zakłócenie normalnego przepływu dopaminy z podwzgórza do przedniego płata przysadki

Należy zauważyć, że w takich przypadkach poziom prolaktyny zazwyczaj nie przekracza 200 ng/ml ¹⁷.

Przyczyny hormonalne

Zaburzenia hormonalne mogą prowadzić do hiperprolaktynemii i galaktocele poprzez różne mechanizmy ¹⁵:

Niedoczynność tarczycy (hipotyreoizm) – niski poziom hormonów tarczycy prowadzi do wzrostu stężenia hormonu uwalniającego tyreotropinę (TRH). TRH nie tylko zwiększa wydzielanie hormonu tyreotropowego (TSH), ale także stymuluje wydzielanie prolaktyny ¹⁸¹⁹.

Wysoki poziom estrogenów – estrogeny powodują hiperprolaktynemię poprzez:

Hamowanie wydzielania dopaminy w podwzgórzu
Bezpośrednią stymulację komórek laktotrofowych ¹

W czasie ciąży wysokie stężenie estrogenów powoduje hiperplazję komórek laktotrofowych, a nawet może prowadzić do wzrostu istniejącego prolaktinoma. Również nadmierne wydzielanie estrogenów z jajników w zespole hiperstymulacji jajników może być związane z hiperprolaktynemią ².

Hipogonadyzm u mężczyzn – niedobór testosteronu może być związany z galaktocele u mężczyzn. Stan ten, określany jako hipogonadyzm męski, często powoduje również powiększenie i tkliwość gruczołów sutkowych (ginekomastię) oraz zaburzenia erekcji i zmniejszenie libido ²⁰²¹.

Przyczyny farmakologiczne

Liczne leki mogą powodować hiperprolaktynemię i galaktocele poprzez różne mechanizmy ¹⁵²²:

Leki przeciwpsychotyczne – najczęstszą przyczyną hiperprolaktynemii indukowanej lekami są neuroleptyki, zwłaszcza klasyczne, które silnie blokują receptory dopaminowe D2 ⁵. Wśród atypowych leków przeciwpsychotycznych risperidon jest najbardziej znany z powodowania tego powikłania ²³.
Leki przeciwdepresyjne – w tym trójpierścieniowe leki przeciwdepresyjne, selektywne inhibitory wychwytu zwrotnego serotoniny (SSRI), inhibitory wychwytu zwrotnego serotoniny i noradrenaliny (SNRI) ²⁴.
Leki przeciwnadciśnieniowe – zwłaszcza metyldopa i werapamil ²⁵.
Opiody – mogą zwiększać poziom prolaktyny ²⁶.
Inhibitory pompy protonowej – opisy przypadków sugerują, że mogą powodować galaktocele ²³.
Leki prokinetyczne – takie jak metoklopramid, które mają działanie antagonistyczne wobec dopaminy ¹⁵.
Doustne środki antykoncepcyjne – regularne stosowanie hormonalnych środków antykoncepcyjnych może prowadzić do zwiększonego poziomu prolaktyny ²⁵²⁷.

Leki te mogą powodować hiperprolaktynemię poprzez ²²:

Bezpośrednie blokowanie receptorów dopaminowych w przysadce
Zmniejszenie wydzielania dopaminy
Stymulację wydzielania serotoniny, która może zwiększać wydzielanie prolaktyny

Inne przyczyny

Hiperprolaktynemia i galaktocele mogą również wynikać z innych stanów ¹⁴²²:

Przewlekła niewydolność nerek – powoduje zmniejszenie klirensu prolaktyny, co prowadzi do podwyższonego poziomu hormonu w surowicy ²⁸.
Marskość wątroby – może wpływać na metabolizm i klirens prolaktyny ²⁸.
Zmiany w ścianie klatki piersiowej – takie jak blizny pooperacyjne, półpasiec lub inne urazy klatki piersiowej mogą stymulować wydzielanie prolaktyny ²⁹.
Nadmierna stymulacja piersi – w tym czynności seksualne, częste badania piersi, tarcie ubrania ²⁹.
Urazy rdzenia kręgowego – mogą zaburzać regulację hormonalną ³⁰.
Niektóre suplementy ziołowe – takie jak kozieradka, anyż lub nasiona kopru włoskiego ³¹.
Stres – przewlekły stres może powodować zmiany w organizmie prowadzące do zwiększonego poziomu prolaktyny ³².

Galaktocele idiopatyczna

W niektórych przypadkach nie można zidentyfikować konkretnej przyczyny galaktocele, mimo przeprowadzenia dokładnej diagnostyki. Stan ten określa się jako idiopatyczną galaktocele lub galaktocele idiopatyczną. Szacuje się, że nawet do 50% przypadków galaktocele może mieć charakter idiopatyczny ²³.

W przypadku idiopatycznej galaktocele może występować ³³²¹:

Prawidłowy poziom prolaktyny w surowicy
Zwiększona wrażliwość tkanki gruczołów sutkowych na prolaktynę, co powoduje, że nawet fizjologiczne stężenie prolaktyny wywołuje galaktocele

Interesującym podtypem jest galaktocele euprolaktynemiczna, gdzie występuje wydzielanie mleka przy normalnym poziomie prolaktyny. Mechanizm tego zjawiska nie jest w pełni wyjaśniony, ale sugeruje się, że może być związany ze zwiększoną wrażliwością tkanki gruczołowej piersi na prolaktynę lub z hiperaktywnością receptorów 5-HT1A ³⁴³⁵.

Mechanizm zaburzeń płodności w hiperprolaktynemii

Hiperprolaktynemia może prowadzić do różnych zaburzeń owulacji, w tym bezowulacji, oligoowulacji, niewydolności fazy lutealnej, zespołu niepękniętego pęcherzyka (LUF) oraz niepłodności o niewyjaśnionej przyczynie ³⁶.

Wpływ na oś podwzgórze-przysadka-gonady

Mechanizm zaburzeń płodności w hiperprolaktynemii obejmuje ³⁷¹⁶:

Zahamowanie wydzielania hormonu uwalniającego gonadotropiny (GnRH) – zwiększone stężenie prolaktyny hamuje pulsacyjne wydzielanie GnRH z podwzgórza.
Zmniejszenie wydzielania gonadotropin – obniżone stężenie GnRH prowadzi do zmniejszenia wydzielania hormonu luteinizującego (LH) i hormonu folikulotropowego (FSH) z przysadki.
Zaburzenia czynności gonad – u kobiet prowadzi to do nieprawidłowości cyklu miesiączkowego, od zaburzeń owulacji do braku miesiączki (amenorrhea); u mężczyzn powoduje zmniejszenie stężenia testosteronu i hipogonadyzm.

Bezpośredni wpływ na gonady

Oprócz działania na poziomie osi podwzgórze-przysadka, hiperprolaktynemia może również bezpośrednio wpływać na czynność jajników ³⁸:

Atrezja rozwijającego się dominującego pęcherzyka
Przerwanie owulacji i prawidłowego rozwoju ciałka żółtego
Przedwczesna inwolucja ciałka żółtego

Badania na modelu szczurzym wykazały, że komórki śródmiąższowe jajnika zawierają specyficzne receptory prolaktyny o wysokim powinowactwie. W tym systemie prolaktyna działa jako silny inhibitor syntezy androgenów stymulowanej przez LH. Zaburzenie produkcji substratów androgenowych hamuje produkcję estrogenów na drodze aromatyzacji ³⁹.

Dodatkowo, receptory prolaktyny o wysokim powinowactwie zostały wykazane na błonach komórek ziarnistych. Inkubacja pęcherzyków z wysokimi poziomami prolaktyny (100 ng/ml) zmniejsza aktywność aromatazy in vitro poprzez antagonizowanie działania FSH ³⁹.

Jednak najnowsze badania sugerują, że główną przyczyną zaburzeń owulacji u pacjentek z hiperprolaktynemią jest zaburzenie pulsacyjności gonadotropin i zaburzenie pozytywnego sprzężenia zwrotnego estrogenów na wydzielanie LH ³⁸.

Mechanizmy molekularne w patogenezie prolaktinoma

Gruczolaki przysadki wydzielające prolaktynę (prolaktinoma) są najczęściej występującymi guzami przysadki i stanowią około 40% wszystkich guzów przysadki ⁴⁰. Mechanizmy molekularne prowadzące do rozwoju tych guzów są złożone i nie w pełni poznane.

Mutacje genetyczne w prolaktinoma

Prolaktinoma mogą wystąpić sporadycznie lub jako część zespołów dziedzicznych ⁴¹⁴²:

Zespoły dziedziczne związane z prolaktinoma:

Zespół mnogiej gruczolakowatości wewnątrzwydzielniczej typu 1 (MEN1) – spowodowany mutacją genu MEN1, kodującego białko menin. Menin ma negatywny wpływ na wzrost komórek poprzez indukcję genów hamujących cykl komórkowy, takich jak CDKN1B (p27KIP1) lub CDKN2C (p18IKN4C). Utrata funkcji jednego allelu DNA genomowego może wzmocnić cykl komórkowy, prowadząc do nowotworowego wzrostu komórek ⁴³.
Rodzinny izolowany gruczolak przysadki (FIPA) – związany z mutacją genu AIP (aryl hydrocarbon receptor-interacting protein) ⁴¹.
Zespół Carneya – wynika z inaktywującej mutacji genu podjednostki regulacyjnej 1A kinazy białkowej A typu (PRKAR1A) ⁴².

Mutacje w sporadycznych prolaktinoma:

Ostatnie postępy w sekwencjonowaniu całego genomu (GWAS) zidentyfikowały mutacje odpowiedzialne za rozwój guzów przysadki. W przypadku prolaktinoma, zidentyfikowano ⁴⁴:

Mutację genu czynnika splicingowego 3B1 (SF3B1) – powodującą substytucję aminokwasów (R625H). Ponieważ białko SF3B1 jest zaangażowane w splicingowanie RNA, mutacja ta może prowadzić do powstania różnych nieprawidłowo złożonych mRNA.
Nieprawidłowo złożone mRNA pochodzące z genu ESRRG – kodującego receptor gamma związany z estrogenem (ERRγ), co prowadzi do zmutowanego białka ERRγ, które ma zwiększone powinowactwo do czynnika transkrypcyjnego PIT1 i silnie wzmacnia zależną od PIT1 transkrypcję genu prolaktyny.
Zmniejszoną ekspresję białka DLG1 – będącego supresorem nowotworowym, co może prowadzić do wzmożonego wzrostu komórek laktotrofowych.

Rola estrogenów w patogenezie prolaktinoma

Estrogeny odgrywają znaczącą rolę w patogenezie prolaktinoma, co może wyjaśniać większą częstość występowania tych guzów u kobiet niż u mężczyzn ⁴⁵:

W eksperymentach na zwierzętach wykazano, że przewlekłe podawanie estrogenów może prowadzić do rozwoju guza laktotrofowego u niektórych gatunków szczurów.
Estrogeny zwiększają ekspresję różnych czynników wzrostu i onkogenów, takich jak czynniki wzrostu fibroblastów (FGF), transformujący czynnik wzrostu β (TGF β) i gen transformujący guzy przysadki (PTTG), które ułatwiają wzrost guza.
Estrogeny mogą powodować zmiany epigenetyczne w różnych tkankach. Jeśli estrogeny zmieniają poziom ekspresji genów, takich jak receptor dopaminy D2, poprzez zmiany epigenetyczne w komórkach przysadki, hormon może wpływać na wzrost komórek laktotrofowych bez mutacji genowej.

Zaangażowanie mechanizmów epigenetycznych w patogenezę prolaktinoma nie jest dobrze scharakteryzowane i wymaga dalszych badań ⁴⁵.

Konsekwencje kliniczne długotrwałej hiperprolaktynemii

Długotrwała, nieleczona hiperprolaktynemia może prowadzić do różnych konsekwencji klinicznych ⁵:

Osteoporoza

Wysokie stężenia prolaktyny, poprzez wpływ na gonadotropiny i wynikające z tego niskie stężenia estrogenów, zmniejszają gęstość kości, zwiększając ryzyko osteoporozy ¹⁵. Jest to szczególnie istotne u nastolatków, gdzie hiperprolaktynemia może być związana z trwałą utratą masy kostnej ⁴⁶.

Zaburzenia płodności

Jak opisano wcześniej, hiperprolaktynemia może prowadzić do zaburzeń owulacji i niepłodności poprzez wpływ na oś podwzgórze-przysadka-gonady oraz bezpośrednie działanie na gonady ³⁶.

Zaburzenia seksualne

U kobiet hiperprolaktynemia może powodować zaburzenia miesiączkowania, od nieregularnych cykli do całkowitego braku miesiączki. U mężczyzn może prowadzić do hipogonadyzmu, ginekomastii, zaburzeń erekcji i zmniejszenia libido ³¹.

Efekty neurologiczne

W przypadku makrogruczolaków przysadki mogą wystąpić objawy neurologiczne związane z uciskiem na struktury otaczające, takie jak nerw wzrokowy, powodując zaburzenia pola widzenia ⁴⁷.

Mechanizm galaktocele – podsumowanie

Patogeneza galaktocele (laktoreji) jest złożonym procesem, w którym główną rolę odgrywa hiperprolaktynemia – podwyższony poziom prolaktyny we krwi. Prolaktyna jest hormonem produkowanym przez komórki laktotrofowe przedniego płata przysadki mózgowej i odpowiada za syntezę i wydzielanie mleka ¹.

Wydzielanie prolaktyny podlega tonicznemu hamowaniu przez dopaminę wydzielaną z podwzgórza. Każdy stan, który zaburza to hamowanie, może prowadzić do zwiększonego wydzielania prolaktyny. Do najczęstszych przyczyn hiperprolaktynemii należą ³⁶:

Zaburzenia metabolizmu dopaminy w ośrodkowym układzie nerwowym (funkcjonalna hiperprolaktynemia)
Gruczolaki przysadki wydzielające prolaktynę (prolaktinoma)
Niedoczynność tarczycy
Stosowanie leków (szczególnie przeciwpsychotycznych, przeciwdepresyjnych, przeciwnadciśnieniowych)

Hiperprolaktynemia prowadzi do galaktocele poprzez bezpośrednią stymulację komórek nabłonkowych gruczołów sutkowych do produkcji mleka, poza okresem ciąży i karmienia piersią. Równocześnie, poprzez hamowanie wydzielania GnRH i gonadotropin, powoduje zaburzenia hormonalne, które mogą manifestować się problemami z płodnością, zaburzeniami miesiączkowania u kobiet oraz hipogonadyzmem u mężczyzn ¹⁶.

Zrozumienie mechanizmów patogenetycznych galaktocele ma kluczowe znaczenie dla właściwej diagnostyki i leczenia tego stanu, którego celem jest nie tylko ustąpienie objawów, ale również zapobieganie długoterminowym konsekwencjom takim jak osteoporoza czy niepłodność ⁵.

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Materiały źródłowe

#1 Galactorrhea – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK537115/
Galactorrhea is milk production from the breast unrelated to pregnancy or lactation. Milk production one year after cessation of breastfeeding is non-lactational and is considered galactorrhea. Various hormones including prolactin, estrogens, thyrotropin-releasing hormone (TRH) can affect the production of milk. […] Prolactin is responsible for the synthesis and secretion of milk. Prolactin is secreted by the lactotroph cells in the anterior pituitary. Dopamine secreted from the hypothalamus inhibits the secretion of prolactin. TRH and vasoactive intestinal polypeptide can stimulate prolactin secretion. Also, nipple stimulation, renal failure, chest wall lesions, and medications can cause hyperprolactinemia. […] Estrogens cause hyperprolactinemia by inhibiting hypothalamic dopamine as well as stimulating lactotrophs directly. In pregnancy, the high levels of estrogen cause lactotroph hyperplasia and can even result in the growth of a preexisting prolactinoma. Excess secretion of estrogen from ovaries in ovarian hyperstimulation syndrome has also been associated with hyperprolactinemia.
#2 Galactorrhea – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/sites/books/NBK537115/
Galactorrhea is milk production from the breast unrelated to pregnancy or lactation. Various hormones including prolactin, estrogens, thyrotropin-releasing hormone (TRH) can affect the production of milk. […] Prolactin is responsible for the synthesis and secretion of milk. Prolactin is secreted by the lactotroph cells in the anterior pituitary. Dopamine secreted from the hypothalamus inhibits the secretion of prolactin. TRH and vasoactive intestinal polypeptide can stimulate prolactin secretion. Also, nipple stimulation, renal failure, chest wall lesions, and medications can cause hyperprolactinemia. […] Estrogens cause hyperprolactinemia by inhibiting hypothalamic dopamine as well as stimulating lactotrophs directly. In pregnancy, the high levels of estrogen cause lactotroph hyperplasia and can even result in the growth of a preexisting prolactinoma. Excess secretion of estrogen from ovaries in ovarian hyperstimulation syndrome has also been associated with hyperprolactinemia.
#3 Evaluation and Treatment of Galactorrhea | AAFP
https://www.aafp.org/pubs/afp/issues/2001/0501/p1763.html
Galactorrhea, or inappropriate lactation, is a relatively common problem that occurs in approximately 20 to 25 percent of women. Lactation requires the presence of estrogen, progesterone and, most importantly, prolactin. Stress, suckling, sleep, sexual intercourse and medications may increase prolactin levels, whereas dopamine inhibits its release. […] The differential diagnosis of galactorrhea includes pituitary adenomas, neurologic disorders, hypothyroidism, numerous medications, breast stimulation, chest wall irritation and physiologic causes. […] Prolactin is normally secreted by the anterior pituitary gland at a low basal rate, with secretion continuously suppressed by prolactin inhibiting factor. […] Prolactin levels cycle and are highest during sleep. Levels in normal nonpregnant women range from 1 to 20 ng per mL (1 to 20 g per L), depending on the laboratory, and may increase to as high as 300 ng per mL (300 g per L) during pregnancy.
#4 Galactorrhea | SpringerLink
https://link.springer.com/10.1007/978-0-306-48113-0_170
Galactorrhea is the spontaneous, nonobstetric production of bilateral white or clear nipple discharge. […] The hormone prolactin is produced in the pituitary gland and promotes milk secretion. […] Prolactin is secreted continuously in nonpregnant women with normal blood levels of 120 ng/ml; levels increase to as high as 300 mg/ml during pregnancy and lactation. […] The most common cause of galactorrhea is idiopathic, in which the prolactin level is normal and there are no other identifiable causes of spontaneous nipple discharge.
#5 Galactorrhoea: Causes and Treatment | Doctor
https://patient.info/doctor/galactorrhoea
Galactorrhoea is milky secretion from the breasts. The term usually refers to milk secretion not due to breastfeeding. It is bilateral and from multiple ducts. The milk volume may be large or small, and milk may be secreted spontaneously or expressed. […] Lactation requires prolactin (PRL). Other hormones are involved in priming the breast prior to lactation: oestrogen, progesterone, insulin, thyroid hormones and glucocorticoids. Oxytocin is involved in milk release. Conversely, oestrogens and progesterone can also have an inhibitory effect on lactation: the fall in levels after delivery facilitates lactation, whilst an injection of oestrogen was used in the past to inhibit lactation. […] PRL is unique amongst the pituitary hormones in that it is regulated by an inhibitory factor from the hypothalamus, whilst the other hormones are regulated by a releasing factor. This inhibitor is mainly dopamine. However, thyrotrophin-releasing factor (TRF) causes the release of not just thyroid-stimulating hormone (TSH) but prolactin too. Hence, acquired hypothyroidism may be associated with elevated PRL. Serotonin may also be involved in PRL release.
#5 Galactorrhoea: Causes and Treatment | Doctor
https://patient.info/doctor/galactorrhoea
There is a physiological increase in PRL levels in response to pregnancy, breast stimulation (especially sucking), stress, sleep, dehydration, sexual intercourse, seizures, exercise and food ingestion. […] Hyperprolactinaemia is the most common cause, and as many as 90% of women with hyperprolactinaemia have galactorrhoea. […] When galactorrhoea is accompanied by amenorrhoea, it is usually caused by hyperprolactinaemia. […] Idiopathic hyperprolactinaemia (40% of cases of hyperprolactinaemia). […] Prolactinomas (PRL levels are usually very high in this case as the tumour causes hypersecretion of PRL). […] The following list is not comprehensive but drugs which raise PRL include: Antipsychotics – the most common drugs to cause hyperprolactinaemia. […] Idiopathic galactorrhoea. When all else has been excluded, what remains is labelled as idiopathic. Female patients with galactorrhoea but normal PRL levels, normal thyroid function and regular periods can probably be observed. […] These depend on the underlying cause. There is probably an increased risk of osteoporosis if hyperprolactinaemia is untreated.
#6 Hyperprolactinemia: Practice Essentials, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/121784-overview
Dopamine has the dominant influence over prolactin secretion. Secretion of prolactin is under tonic inhibitory control by dopamine, which acts via D2-type receptors located on lactotrophs. Prolactin production can be stimulated by the hypothalamic peptides, thyrotropin-releasing hormone (TRH), vasoactive intestinal peptide (VIP), epidermal growth factor, and dopamine receptor antagonists. Thus, primary hypothyroidism (a high TRH state) can cause hyperprolactinemia. […] The primary action of prolactin is to stimulate breast epithelial cell proliferation, thereby inducing and maintaining milk production. Estrogen stimulates the proliferation of pituitary lactotroph cells, resulting in an increased quantity of these cells in premenopausal women, especially during pregnancy. However, lactation is inhibited by the high levels of estrogen and progesterone during pregnancy. The rapid decline of estrogen and progesterone in the postpartum period allows lactation to commence.
#7 Galactorrhea â Zero To Finals
https://zerotofinals.com/surgery/breast/galactorrhea/
Galactorrhoea refers to breast milk production not associated with pregnancy or breastfeeding. Breast milk is produced in response to the hormone prolactin. […] Prolactin is produced in the anterior pituitary gland. It is also produced in other organs, such as the breast and prostate. Prolactin also regulates aspects of immune function and metabolism. […] Dopamine blocks the secretion of prolactin. Therefore, dopamine antagonists (i.e., antipsychotic medications) can result in raised prolactin and galactorrhea. Dopamine agonists (e.g., bromocriptine or cabergoline) can be used to suppress prolactin secretion. […] Galactorrhoea is usually associated with a raised prolactin level (hyperprolactinaemia). […] Prolactin suppresses gonadotropin-releasing hormone (GnRH) by the hypothalamus, leading to reduced LH and FSH release. Therefore, hyperprolactinaemia can also present with menstrual irregularities, particularly amenorrhoea (absent periods), reduced libido (low sex drive), erectile dysfunction (in men), and gynaecomastia (in men).
#8 Galactorrhea | GLOWM
https://www.glowm.com/section-view/heading/Galactorrhea/item/305
Dopamine appears to act on lactotropes by both cyclic adenosine monophosphate (AMP)- and calcium-dependent mechanisms. […] Other agents are involved in the control of prolactin secretion. […] Numerous investigations have been performed to establish the presence and structure of a prolactin-releasing factor. […] Other compounds have been shown to stimulate prolactin secretion, including vasoactive intestinal peptide (VIP) and angiotensin II. […] Several other neurotransmitters appear to be involved in the control of prolactin secretion, including serotonin, endogenous opioid compounds, and histamine. […] In addition to hypothalamic control, prolactin secretion appears to be regulated by both autocrine and paracrine mechanisms. […] Therefore, all these studies would suggest that prolactin regulation is much more complex than a simple inhibition by a PIF.
#9 Galactorrhea: Causes, Symptoms & Treatment
https://my.clevelandclinic.org/health/diseases/17924-galactorrhea
Galactorrhea causes a milk-like discharge to leak from your nipple. It’s unrelated to lactation. […] The most common cause of galactorrhea is a benign (not cancerous) tumor on your pituitary gland. The tumor causes your pituitary gland to make too much prolactin (hyperprolactinemia). Prolactin is the hormone responsible for milk production after you give birth. Excess prolactin tricks your body into thinking it should lactate (or make milk), which is why you leak milk from your nipples. […] The milk that leaks from your breasts when you have galactorrhea is considered milk because its produced by the same hormone (prolactin) that makes breastmilk in women whove just given birth. […] In cases where a pituitary tumor causes galactorrhea, the tumor is usually benign (not cancerous). If the tumor doesnt cause any other complications, your provider may determine that treatment is unnecessary. […] If treating a pituitary tumor is necessary, it usually involves medication to shrink the tumor. In rare cases, you may need surgery or radiation therapy to remove or shrink a pituitary tumor.
#10 From Galactorrhea to Osteopenia: Rethinking SerotoninâProlactin Interactions | Neuropsychopharmacology
https://www.nature.com/articles/1300412
The widespread use of the selective serotonin reuptake inhibitors (SSRIs) has been accompanied by numerous reports describing a potential association with hyperprolactinemia. […] However, there is little awareness of the mechanisms by which SSRIs stimulate PRL release. Hyperprolactinemia may result in overt symptoms such as galactorrhea, which may be accompanied by impaired fertility. […] Through literature review, we explore the possible pathways involved in serotonin-induced PRL release. While the classic mechanism of antipsychotic-induced hyperprolactinemia directly involves dopamine cells in the tuberoinfundibular pathway, SSRIs may act on this system indirectly through GABAergic neurons. Alternate pathways involve serotonin stimulation of vasoactive intestinal peptide (VIP) and oxytocin (OT) release.
#11
https://journals.lww.com/amhe/fulltext/2022/23010/a_case_report_on_escitalopram_induced_galactorrhea.14.aspx
The mechanism of escitalopram-induced galactorrhea is multifactorial. One of the mechanisms is SSRI’s elevated prolactin levels through 5-hydroxytryptamine serotonin (HT) inhibition of the tuberoinfundibular dopaminergic neurons. Another mechanism is, serotonin may directly stimulate prolactin release through the postsynaptic 5-HT receptors in the hypothalamus. […] In the current case report, the finding of escitalopram-induced galactorrhea is contrary to the statement of earlier literature that galactorrhea is more common with fluoxetine and paroxetine. […] Previous reports of escitalopram-induced galactorrhea have been at higher doses of 20 mg/day, but in the current case report patient developed galactorrhea after using escitalopram at a dose of 10mg/day. […] Galactorrhea can occur as a side effect of SSRI and may require stoppage of these otherwise necessary drugs in these patients. […] There is a need to increase awareness of antidepressant-induced galactorrhea among clinicians while evaluating patients presenting with galactorrhea.
#12 From Galactorrhea to Osteopenia: Rethinking SerotoninâProlactin Interactions | Neuropsychopharmacology
https://www.nature.com/articles/1300412
The exact mechanisms through which SSRIs achieve their therapeutic and neuroendocrine effects are not known. SSRIs elevate serotonin levels at the synapse through reuptake blockade of the serotonin transporter (ser-T) which interrupts the normal negative feedback control of presynaptic serotonin release and increases serotonin at the synapse. […] While several SSRIs differentially interact with other neurotransmitter systems, including dopamine and norepinephrine, stimulation of PRL likely involves serotonergic mechanisms, since all SSRIs have been implicated in hyperprolactinemia, regardless of their effects on these other transmitter systems. […] It has long been recognized, based on classic experiments mentioned above, that acute injections of 5-HT or its precursor, 5-HTP, stimulate PRL release. Conversely, blocking either serotonin synthesis or transmission results in a blunted PRL release.
#13 Reversible normoprolactinemic galactorrhea induced by Åuoxetine
https://psychiatry-psychopharmacology.com/en/reversible-normoprolactinemic-galactorrhea-induced-by-suoxetine-132794
Several drugs can cause galactorrhea and it’s etiology needs to be differentiated from other local or neuroendocrinological causes. All conventional antipsychotic drugs block D2 receptors on lactotroph cells and thus remove the main inhibitory influence on prolactin secretion. Tricyclic antidepressants, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors are less frequent causes. There is evidence that serotonin may stimulate prolactin release directly via postsynaptic 5-HT receptors in the hypothalamus or indirectly via 5-HT mediated inhibition of tubuloinfundibular dopaminergic neurons. […] However, galactorrhea due to antidepressants is not consistently associated with elevated prolactin levels, which may suggest still unexplained mechanisms of antidepressant-induced galactorrhea.
#14 Galactorrhea: Rapid Evidence Review | AAFP
https://www.aafp.org/pubs/afp/issues/2022/1200/galactorrhea.html
Galactorrhea is more often the result of hyperprolactinemia caused by medication use or pituitary microadenomas, and less often hypothyroidism, chronic renal failure, cirrhosis, pituitary macroadenomas, hypothalamic lesions, or unidentifiable causes. […] The typical milky nipple discharge associated with galactorrhea can result from a variety of causes, including physical stimulation, endocrinopathies, and pituitary disorders. […] The goal of treatment is to resolve hypogonadal symptoms and reduce tumor size if symptoms are causing significant morbidity (e.g., headache, impotence, infertility, osteoporosis, visual field defects). Galactorrhea itself usually is not an indication for treatment. […] Dopamine agonists (e.g., cabergoline and bromocriptine [Parlodel]) are first-line therapy for hyperprolactinemia caused by a prolactinoma.
#15 Evaluation and Treatment of Galactorrhea | AAFP
https://www.aafp.org/pubs/afp/issues/2001/0501/p1763.html
The most common tumor resulting in hyperprolactinemia is the pituitary prolactinoma, a benign growth of the prolactin-secreting cells of the anterior pituitary gland. […] Pituitary prolactinomas are associated with elevated prolactin levels. […] Any disruption of the communication between the pituitary and hypothalamus glands can result in increased prolactin secretion and milk production. […] Low levels of thyroid hormone result in increased levels of the thyrotropin-releasing hormone, which increases prolactin secretion. […] Galactorrhea can be caused by numerous medications and some herbs. […] Many antipsychotic medications and metoclopramide (Reglan) have lactogenic activity because of their antidopaminergic effects. […] High prolactin levels, through their effect on gonadotropins and resulting low estrogen levels, decrease bone density and thereby increase the risk of osteoporosis. […] Medical treatments for prolactinomas include bromocriptine and cabergoline. These agents activate the lactotroph D2-receptor sites and, similar to dopamine, inhibit the synthesis of prolactin.
#16 Hyperprolactinemia Clinical Presentation: History, Physical, Causes
https://emedicine.medscape.com/article/121784-clinical
Women typically present with a history of oligomenorrhea, amenorrhea, or infertility, which generally results from prolactin suppression of gonadotropin-releasing hormone (GnRH). Galactorrhea is due to the direct physiologic effect of prolactin on breast epithelial cells. […] Prolactin suppresses GnRH, causing a decrease in luteinizing hormone and follicle-stimulating hormone, ultimately leading to decreased serum testosterone levels and hypogonadism. […] Prolactin-secreting adenomas are divided into 2 groups: (1) microadenomas (more common in premenopausal women), which are smaller than 10 mm and (2) macroadenomas (more common in men and postmenopausal women), which are 10 mm or larger. […] When the underlying cause (physiologic, medical, pharmacologic) cannot be determined and an MRI does not identify an adenoma, idiopathic hyperprolactinemia is diagnosed.
#17 Galactorrhea – MD Searchlight
https://mdsearchlight.com/womens-health/galactorrhea/
Galactorrhea, the term for excessive or inappropriate production of breast milk, can be caused by various factors that mainly originate from two areas the hypothalamus and the pituitary gland (in the brain), or by causes not related to these structures. […] When it comes to hypothalamus-pituitary causes, the first common cause is tumors that secrete a hormone called prolactin or Prolactinomas. These are the most common hormone-releasing tumors found in the pituitary gland. If these tumors are smaller than 1 cm, they are called microprolactinomas. If larger than 1 cm, they are known as macroprolactinomas. The prolactin levels in the blood usually correlate with the size of the tumor. […] Other types of non-prolactin-secreting pituitary tumors and disorders affecting the pituitary stalk (the part that connects the hypothalamus and the pituitary gland) or hypothalamus can also cause galactorrhea. They cause a higher level of prolactin (hyperprolactinemia) by interfering with the normal flow of a chemical called dopamine from the hypothalamus to the front part of the pituitary gland, resulting in increased prolactin production, typically less than 200 ng/ml.
#18 Prolactinoma – Endocrine and Metabolic Disorders – MSD Manual Professional Edition
https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/pituitary-disorders/prolactinoma
Galactorrhea is generally due to a prolactin-secreting pituitary adenoma (prolactinoma) but may result from any cause of hyperprolactinemia. […] Prolactin is produced in cells called lactotrophs that constitute about 30% of the cells of the anterior pituitary. […] Prolactin is the hormone most frequently produced in excess by pituitary tumors. […] In contrast to other anterior pituitary hormones, prolactin is regulated primarily by suppression by dopamine, and not by negative feedback from peripheral hormones. […] Nonfunctioning pituitary mass lesions also can increase prolactin levels by compressing the pituitary stalk and thus interrupting the action of dopamine, which normally suppresses prolactin secretion. […] Hyperprolactinemia and galactorrhea also may be caused by ingestion of certain medications, including phenothiazines and some other antipsychotics, certain antihypertensives (especially alpha-methyldopa and verapamil), and opioids.
#18 Prolactinoma – Endocrine and Metabolic Disorders – MSD Manual Professional Edition
https://www.msdmanuals.com/professional/endocrine-and-metabolic-disorders/pituitary-disorders/prolactinoma
Primary hypothyroidism can cause hyperprolactinemia and galactorrhea because increased levels of thyroid-releasing hormone increase secretion of prolactin as well as thyroid-stimulating hormone (TSH). […] Diagnosis of galactorrhea due to a prolactin-secreting pituitary adenoma is based on elevated prolactin levels (typically 5 times normal, sometimes much higher.) […] A trial of dopamine agonist therapy can help distinguish between prolactin-secreting and nonfunctioning lesions; in both types of lesion, prolactin levels decrease after treatment, but prolactin-secreting lesions decrease in size, whereas nonfunctioning lesions do not. […] The initial treatment for both sexes is usually a dopamine agonist such as bromocriptine 1.25 to 5 mg orally twice a day or the longer-acting cabergoline 0.25 to 1.0 mg orally once or twice a week, which lower prolactin levels.
#19 Galactorrhea and What Causes It
https://www.verywellhealth.com/what-is-galactorrhea-2721950
Hypothyroidism when your thyroid produces too little thyroid hormone can cause galactorrhea. This occurs because a person with an underactive thyroid will produce too much of a hormone called thyrotropin-releasing hormone (TRH), which can sometimes stimulate the release of prolactin. […] Tumors in the pituitary gland can cause elevated levels of prolactin, a condition known as hyperprolactinemia. Elevated levels of prolactin due to a pituitary tumor will cause galactorrhea and amenorrhea or no menstrual periods. […] Chronic stress can cause changes in your body that can result in increased levels of prolactin. […] Repetitive and intense nipple stimulation when you are not pregnant or breastfeeding can trigger hormonal changes that result in elevated prolactin levels and galactorrhea. […] Galactorrhea happens when there is too much of the hormone prolactin, which stimulates the production of milk. This may occur due to medication use, stress, overstimulation of the nipples, or health conditions such as hypothyroidism or a pituitary tumor.
#20 Galactorrhea – Symptoms and causes – Mayo Clinic
https://www.mayoclinic.org/diseases-conditions/galactorrhea/symptoms-causes/syc-20350431
Galactorrhea often results from having too much of the hormone that makes milk when you have a baby. This is called prolactin. Your pituitary gland, a small bean-shaped gland at the base of your brain involved with several hormones, makes prolactin. […] Possible causes of galactorrhea include: […] Sometimes healthcare professionals can’t find a cause for galactorrhea. This is called idiopathic galactorrhea. This may mean that the breast tissue is very sensitive to the milk-making hormone prolactin. If so, even typical prolactin levels can lead to galactorrhea. […] In people assigned male at birth, galactorrhea may be linked with too little of the hormone testosterone. Called male hypogonadism, this most often also causes breasts that are enlarged or tender, called gynecomastia. Not being able to get and keep an erection, called erectile dysfunction, and not wanting to have sex also are linked with too little testosterone.
#21 Galactorrhea | Altru Health System
https://www.altru.org/health-library/conditions/galactorrhea
Galactorrhea often results from having too much of the hormone that makes milk when you have a baby. This is called prolactin. Your pituitary gland, a small bean-shaped gland at the base of your brain involved with several hormones, makes prolactin. […] Sometimes healthcare professionals can’t find a cause for galactorrhea. This is called idiopathic galactorrhea. This may mean that the breast tissue is very sensitive to the milk-making hormone prolactin. If so, even typical prolactin levels can lead to galactorrhea. […] In people assigned male at birth, galactorrhea may be linked with too little of the hormone testosterone. Called male hypogonadism, this most often also causes breasts that are enlarged or tender, called gynecomastia. Not being able to get and keep an erection, called erectile dysfunction, and not wanting to have sex also are linked with too little testosterone.
#22 Galactorrhea: Symptoms, Causes in Men and Women, and Treatment
https://www.healthline.com/health/galactorrhea
Galactorrhea is often caused by a prolactinoma. This is a tumor that forms in your pituitary gland. It can press on your pituitary gland, stimulating it to produce more prolactin. Prolactin is the hormone that’s largely responsible for lactation. […] Other tumors can also press on your pituitary gland’s stalk, where it connects to the hypothalamus, an area at the base of your brain. This can stop the production of dopamine. In addition to regulating your emotions, dopamine also helps to keep your prolactin levels in check by decreasing them as necessary. […] If you aren’t producing enough dopamine, your pituitary gland may produce too much prolactin, resulting in nipple discharge. […] Many other conditions can cause you to have too much prolactin. These include: hypothyroidism, which happens when the thyroid gland doesn’t work to full capacity; taking certain high blood pressure medications, such as methyldopa (Aldomet); long-term kidney conditions; liver disorders, such as cirrhosis; some types of lung cancer; taking opioid medications, such as oxycodone (Percocet) and fentanyl (Actiq); taking certain antidepressants, such as paroxetine (Paxil) or selective serotonin reuptake inhibitors (SSRIs), such as citalopram (Celexa); using cocaine or marijuana; taking certain herbal supplements, including fennel or anise seed; taking prokinetics for gastrointestinal conditions; using phenothiazines to get rid of parasites. […] Male hypogonadism refers to having low testosterone. This is one of the more common causes of galactorrhea in males. It can also cause gynecomastia, which enlarges the breasts.
#23 Galactorrhea – Wikipedia
https://en.wikipedia.org/wiki/Galactorrhea
Galactorrhea is also a side effect associated with the use of the second-generation H2 receptor antagonist cimetidine (Tagamet). Galactorrhea can also be caused by antipsychotics that cause hyperprolactinemia by blocking dopamine receptors responsible for control of prolactin release. Of these, risperidone is the most notorious for causing this complication. […] Case reports suggest proton-pump inhibitors have been shown to cause galactorrhea.
#23 Galactorrhea – Wikipedia
https://en.wikipedia.org/wiki/Galactorrhea
Galactorrhea can take place as a result of dysregulation of certain hormones. Hormonal causes most frequently associated with galactorrhea are hyperprolactinemia and thyroid conditions with elevated levels of thyroid-stimulating hormone (TSH) or thyrotropin-releasing hormone (TRH). […] No obvious cause is found in about 50% of cases. […] Lactation requires the presence of prolactin, and the evaluation of galactorrhea includes eliciting a history for various medications or foods (methyldopa, opioids, antipsychotics, serotonin reuptake inhibitors) and for behavioral causes (stress, breast, and chest wall stimulation), as well as evaluation for gestation, pituitary adenomas (with overproduction of prolactin or compression of the pituitary stalk), and hypothyroidism. […] Adenomas of the anterior pituitary are most often prolactinomas. Overproduction of prolactin leads to cessation of menstrual periods and infertility, which may be a diagnostic clue. Galactorrhea may also be caused by hormonal imbalances owing to birth control pills.
#24 Galactorrhea during escitalopram, sertraline, clomipramine treatments used at different times: a case report
https://psychiatry-psychopharmacology.com/en/galactorrhea-during-escitalopram-sertraline-clomipramine-treatments-used-at-different-times-a-case-report-131063
Hyperprolactinemia and galactorrhea are very common in psychiatric patients because of the mechanism of action of antipsychotic drugs on dopamine receptors. […] This side effect could also appear during antidepressant treatment. […] Hyperprolactinemia has been reported to occur as a side effect during treatment with different types of antidepressants including tricyclic antidepressants, selective noradrenaline reuptake inhibitors, selective serotonin reuptake inhibitors (SSRI). […] Besides, galactorrhea due to SRI usage has been proposed to be a result of direct stimulation of serotonin to prolactin release or indirect effect of serotonin as dopamine antagonist. […] In this article; we purposed to discuss galactorrhea side effect of SRIs and resumption of treatment in OCD.
#25 What Is Galactorrhea?
https://www.icliniq.com/articles/endocrine-diseases/galactorrhea
Drugs: Overproduction of the hormone prolactin may also occur to the effect of certain drugs and medications. These drugs include antihypertensives like Methyldopa and Verapamil. Antipsychotic drugs, opioids, and serotonin reuptake inhibitors can also cause an increase in the production of prolactin. Proton pump inhibitors have also been reported to cause galactorrhea. […] Birth Control Pills: Taking birth control pills regularly can also lead to increased levels of prolactin which eventually leads to galactorrhea. […] Disorders Outside Pituitary Gland: Certain disorders that occur outside the pituitary gland can also cause galactorrhea. These disorders include hypothyroidism (underactive thyroid), kidney diseases, liver diseases, certain lung cancers, injury to the spinal cord, chest injuries, etc. In rare cases, stress can also be a causative factor for galactorrhea.
#26 Galactorrhea | 5-Minute Clinical Consult
https://www.unboundmedicine.com/5minute/view/5-Minute-Clinical-Consult/1688531/all/Galactorrhea?q=Cirrhosis
Milky nipple discharge not associated with lactation, defined as 1 year after pregnancy or cessation of breastfeeding. […] Galactorrhea results either from prolactin overproduction or loss of inhibitory regulation by dopamine. […] Hyperprolactinemia can be due to overproduction by malignancy or mass effect, most commonly prolactinoma. […] Hyperprolactinemia secondary to systemic diseases: Hypothyroidism, Chronic renal failure (reduced clearance of prolactin leading to elevated serum levels), Cirrhosis, Adrenal insufficiency. […] Medications/substances: Cardiovascular (-methyldopa, reserpine, verapamil, spironolactone), GI (domperidone, metoclopramide), Herbal (anise [licorice], barley, blessed thistle, fenugreek seed, fennel, goats rue), Illicit (cocaine, marijuana), Antimicrobials (isoniazid, protease inhibitors), Opioids, Psych/neuro (neuroleptics, antipsychotics, stimulants, SSRIs, tricyclic antidepressants, MAOIs), Reproductive (estrogens, copper IUD), DMARDs (azathioprine).
#27 Hyperprolactinaemia and galactorrhoea with combined oral contraceptive pill use: A refresher
https://www1.racgp.org.au/ajgp/2022/june/hyperprolactinaemia-and-galactorrhoea
The proposed mechanism is the stimulatory effect of oestrogen and progesterone on prolactin secretion and the oestrogen-induced proliferation of lactotroph in the anterior pituitary gland. […] The most likely diagnosis in this scenario is a COCP-induced galactorrhoea, after excluding other possible differential diagnoses including pregnancy, intracranial lesions (ie pituitary prolactinoma), breast pathology, idiopathic galactorrhoea and drug-induced hyperprolactinaemia. […] Given that the galactorrhoea only started after the commencement of COCPs, idiopathic galactorrhoea is less likely than COCP-induced galactorrhoea. […] High oestrogen COCPs can result in hyperprolactinaemia and galactorrhoea. Switching to a lower-dose COCP or a progesterone-only pill is a reasonable option to consider.
#28 Galactorrhea | 5-Minute Clinical Consult
https://www.unboundmedicine.com/5minute/view/5-Minute-Clinical-Consult/1688531/all/Galactorrhea
Milky nipple discharge not associated with lactation, defined as 1 year after pregnancy or cessation of breastfeeding. […] Galactorrhea results either from prolactin overproduction or loss of inhibitory regulation by dopamine. […] Hyperprolactinemia can be due to overproduction by malignancy or mass effect, most commonly prolactinoma. […] Hyperprolactinemia secondary to systemic diseases: Hypothyroidism, Chronic renal failure (reduced clearance of prolactin leading to elevated serum levels), Cirrhosis, Adrenal insufficiency. […] Commonly associated with hypothyroidism, chronic kidney disease, hypogonadism, and pituitary adenoma.
#29 Galactorrhea – Humanitas.net
https://www.humanitas.net/diseases/galactorrhea/
Galactorrhea may result from excessive breast stimulation, side effects from medications or disorders of the pituitary gland. […] Galactorrhea is often caused by too much prolactin. Prolactin is produced by the pituitary gland, a gland at the base of the brain that secretes and regulates several hormones. […] Possible causes of galactorrhea include: Medications (sedatives, antidepressants, antipsychotics and high blood pressure drugs), cocaine or opioid use, herbal supplements (fennel, anise or fenugreek seed), birth control pills, underactive thyroid (hypothyroidism), chronic kidney disease, noncancerous pituitary tumor (prolactinoma) or other disorder of the pituitary gland, excessive breast stimulation (such as from sexual activity, frequent breast self-exams, chest rash, prolonged clothing friction), nerve damage to the chest wall (such as from surgery, burns or other chest injuries), spinal cord surgery, injury or tumors.
#30 Galactorrhea in Spinal Cord Injured Patient -Case report-
https://www.e-arm.org/journal/view.php?number=3913
In a few cases, galactorrhea, a secretion of milk or milk-like products from the breast in the absence of parturition, has been reported to occur in women with spinal cord injuries in association with amenorrhea and hyperprolactinemia. One or more of the following factors might play a role in the pathogenesis of this syndrome: Contusion or concussion of the pituitary stalk, Spinal shock with elevation of CNS endorphin level, Irritation of the afferent neural pathway of the thoracic spinal cord. […] We report here one case of galactorrhea and amenorrhea in women that is developed after spinal cord injury. A review of previous case reports and relevant literature is included.
#31 Hyperprolactinemia (High Prolactin Levels) patient education fact sheet | ReproductiveFacts.org
https://www.reproductivefacts.org/news-and-publications/fact-sheets-and-infographics/hyperprolactinemia-high-prolactin-levels/
Hyperprolactinemia is a condition of too much prolactin in the blood, which is abnormal in people who are not pregnant or just had a baby. […] High prolactin levels interfere with the normal production of other hormones, such as estrogen and progesterone. This can change or stop ovulation (the release of an egg from the ovary). […] Ninety percent of women with galactorrhea also have hyperprolactinemia. […] In men, high prolactin levels can cause galactorrhea, erectile dysfunction (inability to achieve and/or sustain an erection during sex), reduced sexual desire, and infertility. […] Some common causes are: Pituitary tumors that are not cancer (prolactinomas), Hypothyroidism (underactive thyroid gland), Medicines given for depression, psychosis, and high blood pressure, Herbs, including fenugreek, fennel seeds, and red clover, Irritation of the chest wall (from surgical scars, shingles, or even a too-tight bra), Stress or exercise (usually excessive or extreme), Certain foods, Nipple stimulation.
#32 Galactorrhea and What Causes It
https://www.verywellhealth.com/what-is-galactorrhea-2721950
Galactorrhea can have a number of triggers and causes, but the root cause is abnormal levels of prolactin, the hormone responsible for breast growth and lactation. […] Prolactin is a hormone produced by the pituitary gland located at the base of your brain. The pituitary gland is part of the neuroendocrine system, which works to regulate many of your bodily functions. Prolactin is normally present in small amounts that fluctuate daily. […] Elevated prolactin levels can inhibit the release of gonadotropin-releasing hormone (GnRH), the hormone that regulates your menstrual cycle, which can lead to irregular periods or stopped periods, a condition known as amenorrhea. This could cause problems if you are trying to get pregnant. […] Galactorrhea is very often caused by certain types of medications that affect your body’s prolactin balance. These medications either interfere with dopamine, the hormone that inhibits prolactin release, or they directly stimulate the pituitary gland to produce prolactin.
#33 Galactorrhea: Causes, Symptoms And Treatment | Netmeds
https://www.netmeds.com/health-library/post/galactorrhea-causes-symptoms-and-treatment?srsltid=AfmBOor4c9t-Kl09yQ4gValzG0nNWxoOBJ-bu_gzOihQsef_xqJBrxeo
Sometimes, the doctor cannot find any exact cause of this condition, and in that case, it is termed as idiopathic galactorrhea. And it means, that the breast tissue is highly sensitive to the milk-producing hormone prolactin in your blood which may even cause galactorrhea if present in normal levels within the body. […] The most primary cause of galactorrhea is a condition that is characterized by the formation of a tumour in the pituitary gland, a small bean-shaped gland at the base of the brain which in turn helps in secreting and regulating several other hormones. When the tumour becomes large and presses the pituitary gland, it is triggered to produce excessive prolactin, a hormone that is chiefly responsible for the secretion of milk for the baby during lactation. […] Apart from males and females, children can also be diagnosed with galactorrhea due to excessive levels of the hormone progesterone in the mother during pregnancy that can enter the placenta and get inside babys blood even before birth. This factor can cause breast enlargement and nipple discharge in children after birth. […] While in some people, it goes away on its own others require timely medical intervention for management. The treatment options for galactorrhea usually focus on managing the underlying symptoms that cause the condition.
#34 A case of cyclophosphamide-induced euprolactinemic galactorrhea – Indian Journal of Dermatology, Venereology and Leprology
https://ijdvl.com/a-case-of-cyclophosphamide-induced-euprolactinemic-galactorrhea/
Galactorrhea is a nonpurulent milky discharge from the breast that occurs spontaneously or with manual expression, in the absence of pregnancy or the postpartum state. It is the most common symptom of hyperprolactinemia, occurring in more than 90% of women with hyperprolactinemia. Common causes of hyperprolactinemia include drugs like dopamine receptor antagonists, opioids, and verapamil, as well as tumours such as sellar and/or pituitary adenomas, hypothyroidism, renal insufficiency, and nipple stimulation. Euprolactinemic galactorrhea refers to galactorrhea not accompanied by hyperprolactinemia. […] After ruling out all possible causes of galactorrhea with normal prolactin levels, she was diagnosed with cyclophosphamide-induced euprolactinemic galactorrhea. […] Euprolactinemic galactorrhea is defined as galactorrhea occurring with normal prolactin levels. This condition has been reported with various drugs, including selective serotonin reuptake inhibitors, tricyclic antidepressants, and domperidone. There is also a single case report of azathioprine-induced euprolactinemic galactorrhea.
#35 A case of cyclophosphamide-induced euprolactinemic galactorrhea – Indian Journal of Dermatology, Venereology and Leprology
https://ijdvl.com/a-case-of-cyclophosphamide-induced-euprolactinemic-galactorrhea/
The mechanism behind euprolactinemic galactorrhea remains unclear. It is hypothesised that increased tissue sensitivity to the metabolic and lactogenic effects of prolactin, as well as hyperresponsive 5-hydroxytryptamine type 1A receptors, could be potential explanations. In our case, serum prolactin levels were normal, and no other systemic cause for the galactorrhea was identified.
#36 Galactorrhea | GLOWM
https://www.glowm.com/section-view/heading/Galactorrhea/item/305
The gene for prolactin has been isolated, cloned, and sequenced. […] Hyperprolactinemia is associated with numerous types of pathology. […] The four most common causes of hyperprolactinemia are central dopamine metabolism disturbance (functional hyperprolactinemia), prolactinomas, hypothyroidism, and drug ingestion. […] It is necessary to evaluate thyroid function in all patients before considering neurosurgical exploration. […] Hyperprolactinemia may not only be associated with galactorrhea but also with numerous ovulatory disorders, including amenorrhea, anovulation, oligo-ovulation, luteal phase defect, luteinized unruptured follicle syndrome, and perhaps unexplained infertility. […] How hyperprolactinemia causes menstrual dysfunction is somewhat unclear. […] It is also possible that hyperprolactinemia may have a direct effect on the ovary.
#37 Clinical manifestations and evaluation of hyperprolactinemia – UpToDate
https://www.uptodate.com/contents/clinical-manifestations-and-evaluation-of-hyperprolactinemia
Hyperprolactinemia causes typical symptoms in premenopausal females and in males, but not in postmenopausal females. […] The mechanism appears to involve inhibition of luteinizing hormone (LH), and perhaps follicle-stimulating hormone (FSH) secretion, via inhibition of the release of gonadotropin-releasing hormone (GnRH). […] The symptoms of hypogonadism due to hyperprolactinemia in premenopausal females correlate with the magnitude of the hyperprolactinemia.
#38 Galactorrhea | GLOWM
https://www.glowm.com/section-view/heading/Galactorrhea/item/305
Suggested mechanisms include atresia of a developing dominant follicle, interruption of ovulation and normal corpus luteum development, and premature involution of the corpus luteum. […] Most data come from the rat model, in which ovarian interstitial cells have been shown to contain a single class of specific high-affinity prolactin receptors. […] Further observations have been made in human oocytes. […] Therefore, it seems possible that hyperprolactinemia may produce alterations in normal reproductive function at the level of the central axis and ovary. […] All these lines of evidence would seem to speak against a primary role of prolactin as a direct disrupter of follicle growth. […] The main cause of anovulation in patients with hyperprolactinemia is an impairment in gonadotropin pulsatility and a derangement in the estrogen positive feedback on LH secretion.
#39 Volume 5, Chapter 32. Galactorrhea
https://www.glowm.com/resources/glowm/cd/pages/v5/v5c032.html
It is also possible that hyperprolactinemia may have a direct effect on the ovary. Suggested mechanisms include atresia of a developing dominant follicle, interruption of ovulation and normal corpus luteum development, and premature involution of the corpus luteum. Most data come from the rat model, in which ovarian interstitial cells have been shown to contain a single class of specific high-affinity prolactin receptors. In this system, prolactin acts as a potent inhibitor of LH-mediated androgen synthesis. Disruption of androgen substrate production inhibits estrogen production by aromatization. Further high-affinity prolactin receptors have been demonstrated on granulosa cell membranes. Coincubation of follicles with high levels of prolactin (100 ng/mL) reduces aromatase activity in vitro by antagonizing the effect of FSH.
#40 Hyperprolactinemia: Practice Essentials, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/121784-overview
Hyperprolactinemia is a condition of elevated serum prolactin. Prolactin is a 198-amino acid protein (23-kd) produced in the lactotroph cells of the anterior pituitary gland. Its primary function is to enhance breast development during pregnancy and to induce lactation. However, prolactin also binds to specific receptors in the gonads, lymphoid cells, and liver. […] Nonpuerperal hyperprolactinemia is a state in which pituitary lactotroph adenomas produce prolactin. These lactotroph adenomas are called prolactinomas and account for approximately 40% of all pituitary tumors. […] However, hyperprolactinemia can also be from a pharmacologic cause or some other pathologic problem of the hypothalamic-pituitary dopaminergic pathways. […] Galactorrhea is due to the direct physiologic effect of prolactin on breast epithelial cells.
#41 Update in Pathogenesis, Diagnosis, and Therapy of Prolactinoma
https://www.mdpi.com/2072-6694/14/15/3604
Prolactinomas are common pituitary neuroendocrine tumors (PitNET) derived from prolactin (PRL)-producing cells that cause hypogonadism and infertility due to hyperprolactinemia. It most frequently occurs in young women and is often associated with galactorrhea and amenorrhea. Most cases are sporadic, but prolactinomas may also occur because of mutations of the multiple endocrine neoplasia type 1 (MEN1) or aryl hydrocarbon receptor-interacting protein (AIP) gene. Medical therapy with a dopamine agonist (DA) is highly effective in the majority of cases. […] Prolactinomas are divided into two subgroups: familial and sporadic. Among the familial cases, the well-known causative mutation is that of MEN1. Indeed, prolactinoma is most frequent in familial PitNETs in patients with MEN1. Although relatively rare, MEN1 gene mutation is found in sporadic prolactinomas. In addition, prolactinoma is reported to occur in families with a mutation in the PRKAR1A (Carney complex), CDKN1B (MEN4), or AIP (FIPA) gene.
#42 Galactorrhea | SpringerLink
https://link.springer.com/10.1007%2F978-3-540-29676-8_670
Prolactin-secreting tumors (prolactinomas) are a common cause of galactorrhea. Most prolactinomas arise sporadically; however, rarely they are a component of a genetic syndrome: Multiple Endocrine Neoplasia-1 (MEN1) and Familial Isolated Pituitary Adenoma (FIPA). […] In MEN1 syndrome mutations in the MEN1 gene cause menin protein disruption. The genetic basis of FIPA is currently unknown. Carney Complex results frequently from an inactivating mutation of the protein kinase A type 1A regulatory subunit (PRKAR1A) gene, and can be associated with hyperplasia of pituitary lactotroph cells and subsequent hyperprolactinemia.
#43 Update in Pathogenesis, Diagnosis, and Therapy of Prolactinoma
https://www.mdpi.com/2072-6694/14/15/3604
The precise molecular mechanism whereby MEN1 gene mutation causes prolactinoma is still obscure. In endocrine cells, MENIN, a protein product of the MEN1 gene, has a negative effect on cell growth via the induction of cell cycle-inhibiting genes such as CDKN1B (p27KIP1) or CDKN2C (p18IKN4C). Thus, MEN1 is recognized as a tumor-suppressor gene. In this sense, a loss-of-function mutation in one allele of genomic DNA can enhance the cell cycle, followed by the tumorous growth of the affected cells. The reason that the germ line MEN1 gene mutation causes a PRL-, growth hormone (GH)- or thyroid stimulating hormone (TSH)-producing PitNET as opposed to any other pituitary tumor is not known. One possibility is that MENIN somehow interacts with PIT1 (POU1F1), the common transcription factor specifically expressed in the somato-, mammo-, and thyrotrope cells, and facilitates PIT1-dependent gene transcription that is related to hormone synthesis and cell growth.
#44 Update in Pathogenesis, Diagnosis, and Therapy of Prolactinoma
https://www.mdpi.com/2072-6694/14/15/3604
Regarding sporadic pituitary tumors, recent advances in genome-wide sequencing (GWAS) have identified the mutations responsible for tumorigenesis. Indeed, USP8 and gsp gene mutations have been found in the substantial parts of corticotrope and somatotroph tumors, respectively. Until recently, however, no driver-gene mutation had been reported for prolactinoma, partly because most patients with the tumor receive medical, not surgical, therapy. Recently, a GWAS analysis of somatotroph tumor cells showed aberrant splicing of various mRNAs, including that of the estrogen-related receptor Î³ (ERRÎ³) gene. Eventually, Li et al. identified a missense mutation of the splicing factor 3B1 gene (SF3B1), causing the amino acid substitution (R625H). Because the SF3B1 protein is involved in splicing nascent RNA, a variety of abnormally spliced mRNA can result from this mutation. In the case of lactotroph tumor cells, abnormally spliced mRNA derived from the ESRRG gene, which encodes ERRÎ³, results in a mutant ERRÎ³ protein, which has shown to have an abnormally high affinity for PIT1 and potently enhance PIT1-dependent PRL gene transcription. Furthermore, the expression of the DLG1 protein is found to be decreased due to the aberrantly spliced DLG1 mRNA. The DLG1 protein is known to have tumor-suppressor properties, and thus its decrease can cause enhanced lactotroph cell growth. Indeed, a prolactinoma-harboring SF3B1 gene mutation is reported to have invasive properties.
#45 Update in Pathogenesis, Diagnosis, and Therapy of Prolactinoma
https://www.mdpi.com/2072-6694/14/15/3604
The pathogenesis of prolactinoma without the SF3B1 mutation is still unknown. One of the major factors promoting lactotroph tumorigenesis is estrogen; indeed, prolactinoma is known to be more frequent in women than in men. In an animal experiment, prolactinoma was reported to develop a lactotroph tumor in some species of rats in which estrogen was chronically administered. Estrogen is known to increase the expression of a variety of growth factors and oncoproteins such as fibroblast growth factors (FGFs), transforming growth factor Î² (TGF Î²), and pituitary tumor transforming gene (PTTG), all of which are known to facilitate tumor growth. More recently, it was reported that estrogen causes epigenetic changes in a variety of tissues other than the adenohypophysis. If estrogen changes the expression level of genes such as the dopamine D2 receptor via epigenetic changes to the pituitary cells, the hormone may influence lactotroph cell growth without a gene mutation. The involvement of an epigenetic mechanism in prolactinoma pathogenesis is not well characterized and awaits further research.
#46 From Galactorrhea to Osteopenia: Rethinking SerotoninâProlactin Interactions | Neuropsychopharmacology
https://www.nature.com/articles/1300412
Taken together, pharmacologic and anatomic data indicate that the PVN represents a major regulatory site of serotonin-induced PRL release, although the relative role of VIP and OT pathways in this response is not established. […] An alternate path for serotonin-induced PRL release is inhibition of the tuberoinfundibular dopamine cells (TIDA). However, there is little synaptic contact between serotonergic fibers and the dopamine cells, indicating that if direct inhibition of dopamine cells occurs, it is through volume transmission of serotonin in the region. […] Hyperprolactinemia in adolescents is associated with persistent bone loss. […] This review highlights possible mechanisms and manifestations of serotonergic stimulation of PRL, considering them in the context of SSRI use. There are a number of different pathways through which SSRIs may cause PRL abnormalities, including release of a PRF such as VIP or OT, and the inhibition of the TIDA system.
#47 Galactorrhea | GLOWM
https://www.glowm.com/section-view/heading/Galactorrhea/item/305
The primary mode of therapy for the treatment of functional hyperprolactinemia involves the use of dopamine agonists. […] Bromocriptine was the first compound approved for the treatment of hyperprolactinemia in the United States. […] Cabergoline has been shown to be more effective than bromocriptine in a multicenter, 24-week trial of 459 hyperprolactinemic women randomized to either cabergoline or bromocriptine. […] The patient with radiographic evidence of microadenoma may be treated in an identical manner to the patient with functional hyperprolactinemia. […] The patient who fails to show suppression of prolactin levels or shrinkage of tumor with bromocriptine therapy possibly houses a non-endocrine-secreting tumor or one that produces another trophic hormone.