Prolactin

Unique among the pituitary hormones, prolactin secretion is tonically inhibited by the hypothalamus. Prolactin is a single-chain protein secreted by the anterior pituitary whose principal physiologic effects involve breast development and milk production. Consistent with its role in lactogenesis, prolactin secretion increases during pregnancy Dopamine has many characteristics of the hypothalamic inhibitory factor, although it is not found in the hypothalamus.

Ans.A. Dopamine

• “Dopamine is the primary neuroendocrine inhibitor of the secretion of prolactin from the anterior pituitary gland and hence causes hypoprolactinemia, not hyperprolactinemia”

Macroadenoma > 1 cm is associated with bad prognosis [Ref: Dewhurt’s text book of Obs Gynae 7/e p. 255-256]

• Prolactinomas are prolactin secreting tumours of the pituitary  It is a benign tumour

They are the most common type of pituitary tumour0

They are _.five times more common in women

• Prolactittomas are an important cause of infertility in women

–      They constitute about 1/3^rd cases of infertility

• Treatment of prolactinomas restores fertility

– Women undergoing infertility t/t for prolactinoma gets pregnant

• However an important point to note is that pregnancy causes growth of prolactinomas

–The rising estrogen levels during pregnancy have a marked stimulatory _effect on normal lactotrophs. – Hypertrophy and hyperplasia of the lactotrophs results in an upto 1.5 fold increase in pituitary size. – Such increase in size may also occur with prolactinomas mostly in the second and third trimesters.

“About 1.2% microprolactinomas and about 24% of macro- prolactinomas increase in size during pregnancy”.

Management of prolactinoma in pregnancy

• Microprolactinoma

-For women with microprolactinoma the subsequent risk of adenomas growth during pregnancy appears to be 1%, once the drug is discontinued

– In these cases drug is discontinued once the patients is pregnant

– Symptomatic follow up should be done each trimester, and treatment is reinitiated, only if symptoms of tumour growth develops.

• Macro prolactinoma

For women with maeroprolactinoma there is 23% risk of tumour enlargement.

– In these cases optimal choice of t/t is more difficult to determine. The patient should be advised to reduce the tumour size by medical treatment prior to pregnancy or at least responsiveness of the tumour to medical treatment should he established.

– After conception bromocriptine may be stopped or continued during pregnancy depending on the aggressiveness of the tumour.

– It symptoms of rumour appear of regrowth develops therapy is reinitiated. If medical t/t _.fails surgery is recommended.

Treatment during pregnancy

– Treatment of women with lactotroph adenomas should begin before conception with advice to the woman and her partner about the risks of pregnancy to her and the .fetus.

– The woman is then monitored during pregnancy and, if relevant, nursing.

– The approach outlined here is consistent with the 2011 Endocrine Society Clinical Practice Guidelines on the  diagnosis and treatment of hyperprolactinenzia.

– When a dopamine agonist is needed to lower the serum prolactin concentration to permit ovulation, we suggest bromocriptine rather than cabergoline, because of the greater certainty that it does not cause birth defects, as described above. However, if a woman cannot tolerate bromocriptine, we recommend cabergoline. Microadenomas

A woman who has a lactotroph microadenoma should be told that the risk of clinically important enlargement of

her adenoma during pregnancy is very small (1.2%) and that it should not be a deterrent to becoming pregnant. – She should also he told that bromocriptine or caber’ oline will likely be effective if symptoms do occur.

– If she is willing to take this risk, she should be given bromocriptine or cabergoline before pregnancy in whatever dose is necessary to lower her serum prolactin concentration to normal.

– Bromocriptine is still the preferred drug Pr this purpose _.for most women because of the greater experience with it. When the serum prolactin concentration is normal and menses have occurred regularly for a few months, the woman can attempt to become pregnant. Bromocriptine should be discontinued as soon as pregnancy has been confirmed, an approach that is safe given the lack of apparent toxicity during the first trimester.

If the adenoma is not responsive to a dopamine agonist, ovulation can usually be induced by administration of other ovulation induction agents.

During the pregnancy, the woman should be seen every three months and asked about headaches and changes in vision.

If no symptoms occur, serum prolactin can be measured two months after delivery or cessation of nursing, and if it is similar to the pretreatment value, the drug can he resumed.

Treatment is initiated during pregnancy when there is tumour growth or symptoms develop.

Macroadenomas

– A woman who has a lactotroph macroadenoma should be advised of the relatively higher risk of clinically important tumor enlargement during pregnancy (23%).

– Advice and monitoring depend upon how large the adenoma is.

If the adenoma does not elevate the optic chiasm

– Treatment with bromocriptine or cabergoline for a sufficient period to shrink it substantially should reduce the chance of clinically important enlargement during pregnancy.

Once this has occurred, the woman can attempt to become pregnant; the dopamine agonist should be discontinued when pregnancy has been confirmed.

Monitoring during pregnancy should be similar to that described above for women with microadenomas.

A perceived change in vision should be assessed by a neuroophthalmologist, and an MRI should be performed if an abnormality consistent with a pituitary adenoma is confirmed.

If the adenoma has enlarged to a degree that could account for the symptoms, the woman should be treated with bromocriptine throughout the remainder of the pregnancy, which will usually decrease the size of the adenoma and alleviate the symptoms.

– If the adenoma does not respond to bromocriptine, cabergoline may be successful. If cabergoline is not successful, transsphenoidal surgery could be considered in the second trimester if vision is severely compromised. In comparison, surgery for persistent visual symptoms in the third trimester should be deferred until delivery if possible.

• If the adenoma is very large or elevates the optic chiasm

– Pregnancy should be strongly discouraged until the adenoma has been treated by transsphenoidal surgery, and perhaps postoperatively by radiation.

– Postoperative treatment with bromocriptine or cabergoline may also be helpful in reducing adenoma size further and lowering the serum prolactin concentration to normal.

– Such a regimen reduces the chance that symptomatic expansion will occur during pregnancy, but it may still occur.

• Pregnancy should also be discouraged in a woman whose macroadenoma is unresponsive to bromocriptine and cabergoline, even if it is not elevating the optic chiasm, until the size has been greatly reduced by transsphenoidal surgery, because medical treatment would not likely be effective if the adenoma enlarges during pregnancy.

Breast feeding

– Breast feeding does not increase the risk of lactotroph adenoma growth.

-Therefore, breastfeeding is an option for women with micro- and macroadenomas that remained stable in size during pregnancy.

– However, dopamine agonist treatment should be withheld until breastfeeding is completed.

– In contrast, breastfeeding is contraindicated in women who have neurologic symptoms at the time of delivery (suggesting tumor growth), because they should be treated with a dopamine agonist.

We are unable to comprehend the option ‘c’

• Prolactinomas are classified as macroprolactinomas only when they are > 10 mm or 1 cm.

– May be , the correct option would have been prolactinoma > 10 mm are associated with worse prognosis. – Macroprolactinomas are definityly associated with worse prognosis during pregnancy.

– “Approximately 23% macroprolactinomas increase in size during pregnancy as compared to 1-2 microprolactinomas”.

Increase in prolactin level associated with worse prognosis.????

• We are not sure of this option
• Increased prolactin levels are definitely associated with worse prognosis in nonpregnant women whether, it retains the same prognostic significance during pregnancy is doubtful because during pregnancy there is significant increase in prolactin level. It becomes quite difficult to distinguish whether this elevation is due to tumour activity or pregnancy itself.

Dewhurst says

“Prolactin levels should not be checked as they increase by as much as 10 folds by 25^th week of gestation”.

Williams obstetrics says

“Serial serum prolactin levels are not recommended because of normal increase during pregnancy”.

Increased estradial [Ref: Harrison 17⁶/e p. 2205; Ganong 23^rd/e p. 401]

• Prolactin is a polypeptide produced by the lactotrophs of the pituitary.
• It is responsible _.for the initiation and maintenance of lactation.
• As with several pituitary hormones, prolactin is secreted in a circadian_, fashion with the highest levels being attained during sleep and a nadir occurring between 10 am and noon.
• Prolactin is secreted in a pulsatile _.fashion, the amplitude and frequency of which not only varies throughout the day but is also impacted upon by a variety of physiology stimuli i.e., suckling, stress and increased level of ovarian steroids primarily estrogens.
• “The general view is that lactotrophs have spontaneously high secretary activity”.
• Therefore pituitary prolactin secretion is under a tonic and predominantly inhibitory control exerted by the hypothalamus.

– Hypothalmus releases prolactin inhibitory factor (PIF) which inhibits prolactin release.

– PIE is actually dopamine and it suppresses prolactin synthesis and secretion by means of D2 receptors.

– These actions constitute the physiologic basis of therapeutic effect of dopamine agonists in hyperprolactinemia.

• Prolactin acts on the breast tissue where in the setting of estrogen priming, it stimulates lactation. Effect of physiological hormones on prolactin secretion
• Glucocorticoids seem to have an inhibitory role on PRL secretion.

– These hormones stimulate the differentiation of somatotrophs but suppress that of lactotrophs.

– Long-term elevation of the serum glucocorticoid levels by chronic administration of corticotrophin (ACTH) or hydrocortisone or by prolonged stress decreases PRL secretion.

• Estrogens and thyroid hormones have opposite effects on PRL  synthesis and release.

– “Estrogen increases prolactin level^Q by acting at both pituitary and hypothalamic level”

– At pituitary level it increases prolactin secretion by controlling PRL gene expression and modifying its sensitivity to physiological stimuli.

– At hypothalamic level it inhibits the activity of all three types of hypothalamic neuroendocrine dopaminergic neurone.

– Low thyroxine (T4) and triiodothyronine (T3) levels increase TRH-induced PRL secretion, whereas high T4 and T3 levels inhibit PRL mRNA accumulation and release.

An important point

Increased estrogen causes hyperprolactinemia

But

Hyperprolactinemia causes decrease in estrogen

• Prolactin also acts at the hypothalamus to inhibit the secretion of gonadotropin releasing hormone (GnRH).

– Inhibition of GnRH results in a decrease in the release of LH and FSH from the anterior pituitary. In females

– This leads to decreased in estrogen and progesterone synthesis and secretion by the ovaries and a failure of ovarian _.follicular maturation.

In males

– This leads to decrease in testicular production and synthesis of testosterone and a halt in spermatogenesis.

Ans is a, b and c Prolactin; HPL; and Progesterone

Lactation can be divided into 3 stages :

Stage I : Mammogenesis – Mammary growth and development

Hormones responsible :

Growth                        Main hormone                                          Supporting hormones

Ductal growth             Oestrogen                                        Growth hormone and glucocorticoids

Alveolar growth          Progesterone                                   Prolactin, prednisolone and other

(in the oestrogen primed breast)                                       growth promoting factors

Stage ii :                 Lactogenesis : Initiation of milk secretion

Main hormone responsible : Prolactin

Although prolactin levels continue to rise as pregnancy advances, placental sex steroids block prolactin induced secretory activity of-the glandular epithelium. Therefore, lactation is not initiated until plasma estrogens progesterone, and human placental lactogen (hPL) level fall after delivery.”

Supporting hormones : • Estrogens

• Progestins
• Human placental Lactogen

Stage

Galactopoiesis or Maintenance of established milk secretion is mainly by suckling°. Hormones responsible :

• Prolactin°                                   • Oxytocin°
• Growth hormone°                       • Thyroxine/Parathyroid hormone°
• Cortisol°                                     • Insulin°

The diagnosis of hyperprolactinemia is made by estimation of fasting morning prolactin.

Maternal plasma levels of prolactin increase markedly during normal pregnancy and concentrations are usually 10-fold greater at term—about 150 ng/mL—compared with nonpregnant women. Paradoxically, plasma concentrations decrease after delivery even in women who are breast feeding.

During early lactation, there are pulsatile bursts of prolactin secretion in response to suckling. 

Prolactinoma is a tumor arising from lactotrope cells of pituitary. Women usually present with amenorrhea, infertility, and galactorrhea. If the tumor extends outside the sella, visual field defects or other mass effects can occur. Diagnosis of prolactinoma is likely with a PRL level >200μg/L.

Oral dopamine agonists (cabergoline and bromocriptine) are the mainstay of therapy for patient with micro or macroprolactinomas. They suppress PRL secretion and synthesis as well as lactotrope cell proliferation. Indications for surgical adenoma debulking include dopamine resistance or intolerance, presence of an invasive macroadenoma with compromised vision that fails to improve after drug treatment. 

Ref: Harrison’s Internal Medicine, 18th Edition, Pages 2261-2263, 2888, 3388 and 3389, Chapter 339

The function of dopamine is to supress the prolactin secretion. Prolactin agonists reduce secretion of prolactin and antagonists increase the secretion of prolactin. Cabergoline is a long acting dopamine agonist. The drug suppresses prolactin secretion. Used to treat prolactinoma. All others can cause increased secretion. High prolactin levels are also associated with Hypothyroidism.

TRH is derived from a pro-TRH peptide. Like other hypothalamic-releasing hormones, TRH reaches the anterior pituitary via the hypothalamic-pituitary portal circulation. It interacts with specific receptors on pituitary thyrotrophs to release TSH and on mammotrophs to release prolactin.

Ref: Textbook of Endocrine Physiology edited by William J. Kovacs, Sergio R. Ojeda, 2011, Page 324; Guyton’s physiology, 22nd edition, Table 74-1 Page 907

B i.e. Dopamine

Dopamine acts as hypothalamic prolactin inhibiting hormoneQ and decreases prolactin secretion.

Ans. is ‘d’ i.e., Bromocriptine

o Prolactin is under predominant inhibitory control of hypothalamus through prolactin releasing inhibitory hormone (PRIH).

o PRIH is a dopamine that acts on pituitary lactotrope D, receptor.

• So, Dopaminergic agonists decrease plasma prolactin levels. These agonists are :

       Dopamine                        Cobergoline

       Bromocriptine                  Apomorphine

• Dopaminergic antagonists and DA depleters will increase prolactin level

Dopaminergic antagonists are : Dopamine depleters are :

o Chlorpromazine                                    o Reserpine

o Haloperidol                                         o Methyl dopa

o Metoclopramide

Ans. is ‘c’ i.e., Cabergoline

Both Bromocriptine and cabergoline can be used as both decrease prolactin levels, however, cabergoline is better tolerated.

Ans. is ‘a’ i.e., Cabergoline

Ans. is ‘d’ i.e., Lasix

Drug causing hvperprolactinemia and galactorrhea.

o Phenothiazines (chlorpromazine)              o alpha-methylodopa              o Amitriptyline, amoxapine          o Antiestrogen

o Butyrophenones (haloperidol)                   o Reserpine                            o Fluoxetine

o Metoclopramide                                     o Opiates                               o Verapamil

o Thioxanthenes                                   o Cimetidine, ranitidine             o Estrogen

Answer is A (Bromocriptine):

Bromocriptine is a potent dopamine agonist. It decreases prolactin release from pituitary by activating inhibitory dopaminergic receptors on lactotrope cells, a strong anti-galactopoietics action.

All others are known to cause increased Prolactin.

Answer is C (Prolactin estimation):

Basal fasting morning prolactin levels should be measured to assess hypersecretion – Harrison

Answer is A (Prolactin):

The pituitary gland sits cradled within the sella turcica. The most common cause of a mass in the sella turcica is a Pituitary adenoma. The most frequent type of hyper-functioning pituitary adenomas are Prolactinomas that account for approximately 30 percent of all clinically recognized pituitary adenomas. Elevated levels of Prolactin are characteristic findings

‘Hyperprolactinemia is the most common pituitary hormone hypersecretion syndrome in both men and women. Prolactin secreting pituitary adenomas (Prolactinomas) are the most common cause’ – Harrison

Answer is C (Prolactinoma):

`Prolactinomas (Lactotroph Adenomas) are the most frequent type of hyperfunctioning pituitary adenomas, accounting for about 30% of all clinically recognized pituitary adenomas’ – Robbins

Answer is B (Prolactinoma):

Menstrual cycle disturbance in the form of amenorrhea along with galactorrhea suggests a diagnosis of hyperprolactinemia.

Amongst the options provided the tumor most likely to produce above endocrine manifestation is a prolactinoma.

Prolactinomas: Most common functional pituitary adenomas Q

Answer is A (Pituitary adenoma):

Pituitary adenomas produce excess prolactin which causes hypogonadism, decreased levels of testosterone and explains loss of erection.

Pituitary adenomas (Prolactinomas) lead to an excess of prolactin. This inhibits hypothalamic release of LHRII resulting in defective LH & FSH secretion. Defective LH & FSH secretion in turn result in decreased levels of estrogen in females & testosterone in males. This is how prolactin excess can cause hypogaonadism

In men prolactin excess can cause In females prolactin excess can cause

Decreased Libido, impotence                     Irregular mensus (amenorrhea)

Infertility.                                                Infertility despite regular mensus.

This explains this 30 year old male’s complaints of loss of erection & his low testosterone & high prolactin levels. Testicular failure explains both loss of erection and low testosterone levels but not the high prolactin levels

Ans. D: Prolactin

Ans. A: TRH

Pituitary prolactin secretion is regulated by neuroendocrine neurons in the hypothalamus, the most important ones being the neurosecretory tuberoinfundibulum (TIDA) neurons of the arcuate nucleus, which secrete dopamine to act on the dopamine-2 receptors of lactotrophs, causing inhibition of prolactin secretion.

Thyrotropin-releasing factor (thyrotropin-releasing hormone) has a stimulatory effect on prolactin release. Vasoactive intestinal peptide and peptide histidine isoleucine also help to regulate prolactin secretion in humans.

Ans. D: Prolactinoma

Hyperprolactinemia may present with galactorrhea, amenorrhea (females) and hypogonadism Galactorrhea rarely occurs in men and only does so, if gynaecomastia has been induced by hypogonadism