1) Prolactinomas are the most common type of pituitary adenoma, accounting for about 40% of cases. They secrete excess prolactin which can lead to menstrual irregularities, infertility, and hypogonadism. 2) Pregnancy is a hyperestrogenic state that can cause pre-existing prolactinomas to develop or expand due to pituitary hyperplasia. This can increase the risk of complications like visual loss. Hyperprolactinemia has also been linked to gestational diabetes. 3) Treatment of prolactinomas during pregnancy involves dopamine agonists which help control hormone levels and tumor growth with minimal risk. Patients require close monitoring, especially those with macroprolactin

1. PROLACTINOMA AND
PREGESTATIONAL DIABETES
MELLITUS

2. • Prolactinomas are adenomas which arise from lactotroph cells in the pituitary gland that secrete
prolactin. Prolactinoma is the most frequent pathological cause of hyperprolactinemia and the
most common type of pituitary adenoma, accounting for about 40 % of the cases
• Prolactinomas are the most common hormone-secreting pituitary tumors,accounting for
approximately 40% of all pituitary tumors (2,6) In adults, prolactinomas have an estimated
prevalence of 60-100 per million population (7,8), and in a population from three different
districts of Belgium, prolactinomas have been reported to represent 73.3% of all pituitary
adenomas, with a higher prevalence in women (78.2%) (9). Between the age of 20 and 50 years,
the ratio between women and men is estimated to be 10:1
• The signs and symptoms found in hyperprolactinemic patients are associated with hypogonadism,
hypogonadotropes and galactorrhea. Hypogonadism can cause menstrual irregularities, infertility,
sexual dysfunction and amenorrhea in women
• (Araujo, Belo dan Carvalho, 2017; Vilar et al., 2018).

3. • Pregnancy is a hyperestrogenic condition that can predispose to the
development of pre-existing prolactinomas
• During pregnancy, the pituitary gland undergoes global hypeplasia due to a
progressive increase in serum estrogens level that may lead to increase of
the tumor volume with potential mass effect and visual loss
• Indeed, hyperprolactinemia in pregnancy has been related to the
pathogenesis of impaired glucose tolerance and hyperinsulinemia up to
overt insulin resistance which poses significant challenge to
endocrinologists.
• (Almalki et al., 2015; Auriemma et al., 2019; Bachmeier, Snell dan Morton, 2019; Vroonen, Daly dan Beckers,
2019).

4. • Prolactinoma diagnosis is based on clinical, laboratory and imaging
characteristics
• Female patients with prolactinoma will have difficulty conceiving
children and maintaining a pregnancy, so appropriate management
should be indicated to minimize maternal-fetal complications.
• (Glezer dan Bronstein, 2020).

5. Epidemiology
• Overall, the prevalence of PRL-secreting tumors ranged from 25 per 100,000 to
63 per 100,000. The prevalence of symptomatic microprolactinomas and
macroprolactinomas is approximately 40 and 10 per 100,000, respectively
• The peak age of occurrence in women occurs at approximately 30 years, while
most men are diagnosed after age 50 [15].
• The ratio between macro- and microprolactinomas is approximately 1:8 in
women, whereas it is inverted in men (macroadenomas in 80% of cases) [14].
• The standard annual incidence rate ofprolactinomas ranged from 2 to 5 new
cases/100,000, and the
• value is 3-times higher in women than in men
• Most studies also reported an increase in this incidence rate over time, possibly
indicating improved disease recognition
• (Chanson and Maiter, 2019).

6. • Regardless of its cause, hyperprolactinemia interferes with pulsatile
GnRH secretion and inhibits LH and FSH secretion, thus causing
hypogonadism in both sexes and infertility. In addition, the mass of a
prolactinoma may cause compressive effects on parasellar structures
and hypopituitarism.
• in women, most prolactinomas are microadenomas and induce
menstrual changes (oligoamenorrhea), galactorrhea, and infertility. In
postmenopausal women, the clinical signs are mainly due to the mass
effect of the adenoma.
• (Halperin Rabinovich et al., 2013).

7. • The increasing amount of estrogen produced by the placenta stimulates
lactotroph hyperplasia and a gradual increase in PRL levels over the course of
pregnancy
• Magnetic resonance imaging (MRI) scans show a gradual increase in pituitary
volume over the course of gestation, beginning by the second month and peaking
the first week postpartum with a final height reaching to almost 12 mm
• patients with clinically significant tumor enlargement criteria were quite variable
and in most of those series, symptoms consisted of progressive, severe
headaches and/or visual field defects.
• (Molitch, 2015).

8. • During pregnancy, physiological hyperplasia of lacto- troph cells leads
to pituitary hypertrophy and elevation of prolactin levels by up to 10-
fold. Moreover, pregnancy is an important hyperestrogenic state that
can also influence the evolution of preexisting prolactinomas. ever,
the risk of tumor expansion during pregnancy is low in
microprolactinomas (2.7%) and previously treated
macroprolactinomas (4.8%); tumor expansion is, how- ever,
significantly more frequent in untreated macroprolactinomas (22.9%)
• (Vroonen, Daly dan Beckers, 2019)

9. • Since there are causes of hyperprolactinemia other than prolacti- noma(Box) a careful history, examination,
andmeasurement ofse- rumthyrotropin and creatinine are required.23,24AnMRI will deter- mine whether a
tumor is present and its size. More than 90% of prolactinomas are microadenomas. if no tumor is found, the
hyperprolactinemia is idiopathic
• In case the patient becomes symptomatic with visual disturbance or progressive headaches, an MRI without
gadolinium (not a CT) should be performed to assess changes in tumor size
• If the prolactin level is more than 200 μg/L (to convert to pmol/L, multiply by 43.478), it is almost always due
to production by a prolactinoma rather than stalk compression.26 If thetumor is very large (>3 cm), the very
high prolactin levels (usually >10000 μg/L) may rarely saturate the antibodies in some assays, leading to arti-
factually lowor normal results (the “hook effect”) and prolactin lev- els should be rerun at 1:100 dilution to
exclude this
• It is recommendable to intensify clinical follow-up in macroadenomas during pregnancy, starting with a
visual field evaluation followed by an unenhanced MRI in women experiencing severe headaches
• (Almalki et al., 2015; Molitch, 2017; Vroonen, Daly dan Beckers, 2019).

10. • The goals of prolactinoma management include normalizing serum
prolactin levels and reducing tumor size in macroprolactinomas,
restoring eugonadism and reversing the mass effect that causes
headache, visual disturbances, and hypopituitarism. Treatment
modalities consist of DA (dopamine agonist/dopamine agonist),
neurosurgery, and radiotherapy
• (Glezer dan Bronstein, 2015).

11. • AD is the gold standard treatment for prolactinoma, because its use is able to control hormonal secretion
and tumor growth in about 80% of cases. Cabergoline (CAB), a specific agonist of the D2 receptor has better
tolerability. In addition to CAB, the use of bromocriptine resulted in normal serum prolactin levels in 80% of
microprolactinomas and 70% of macroprolactinomas, whereas with CAB this goal was achieved in 85% of
patients.
• Bromocriptine It is started as 1.25 mg at bedtime or after dinner daily for one week then increased to 1.25 mg
2 times a day (after breakfast and dinner). The dose should be increased every 4 weeks if prolactin level is not
normalized up to a maximum dose of 5 mg two times a day. If bromocriptine is unsuccessful, cabergoline
should be started
• The most common side effects of AD use are nausea, vomiting, and postural hypotension. Less commonly it
can cause nasal congestion, cramping, and psychiatric disorders. Bromocriptine has been shown to cross the
placental blood barrier in human studies; cabergoline has been shown in animal studies but data in humans
is scant.
• In more than 6000 pregnancies, bromocriptine has not been associated with adverse pregnancy outcomes
Bromocriptine has been used throughout gestation in more than 100 women, with no abnormalities noted
in the infants except for 1 with an undescended testicle and another with a talipes deformity.
• (Glezer dan Bronstein, 2015; Huang dan Molitch, 2019; Yatavelli dan Bhusal, 2021).

12. • In women taking bromocriptine during early pregnancy, the rates of
abortion, ectopic pregnancy, or congenital malformations are not
higher than in the general population. In macroprolactinomas, in
addition to surgical management, bromocriptine is considered the
drug of first choice, and usually reduces the size of the adenoma and
relieves symptoms. Cabergoline may be considered if the adenoma
does not respond to bromocriptine
• (Almalki et al., 2015).

13. • Surgery, usually with a transphenoidal approach, is indicated for
patients with resistance or intolerance to AD; macroprolactinoma
with chiasm compression and visual disturbances without rapid
improvement with medical treatment; symptomatic apoplexy;
cerebrospinal fluid leakage, which may occur in cases of sphenoid
sinus invasion; and tumor shrinkage with the use of AD. Prolactinoma
is one of the most radioresistant pituitary tumors. Therefore,
radiation therapy is only indicated to control tumor growth in cases of
resistance to AD that cannot be controlled surgically
• (Glezer dan Bronstein, 2015)

14. • (Almalki et al., 2015)

15. • Patients with microprolactinomas (MICs) or enclosed
macroprolactinomas (MACs) should be followed each trimester, with
attention to headache and visual impair ment (217). In the pres ence
of those complaints, sellar MRI without contrast, preferably after the
first trimester, should be performed, and BRC reintroduc tion is
indicated if tumor growth is related to the clinical findings (217). In
cases of BCR intolerance, CAB, although off-label, could be used
instead (217,219,222). On the other hand, in pa tients with expanding
MACs, DA maintenance throughout pregnancy should be evaluated
by an expert (217,219).
• (Vilar et al., 2018).

16. Algorithm suggested for the prolactinoma management during
pregnancy (PRL: prolactin; BCR: bromocriptine; MRI: magnetic
resonance imaging)
(Vilar et al., 2018)

17. • The majority of patients with microprolactinomas have an excellent
prognosis. These patients can be managed medically for extended
periods. Macroprolactinomas, on the other hand, can grow over time
and require more aggressive treatment. The growth rate of
macroprolactinomas is unpredictable, and the patient must be closely
followed up. The decision to taper medical therapy requires sound
judgment because the tumor can grow in size, without treatment
(Yatavelli dan Bhusal, 2021).

18. • Under normal conditions without pregnancy, prolactin has an important role in
regulating insulin sensitivity and glucose metabolism by increasing the proliferation of
pancreatic beta cells, increasing insulin secretion, and regulating the immune system.
However, it should be underlined that the condition of a physiological increase in
prolactin hormone is very different from the condition of a pathological increase in
prolactin.
• PRL excess may promote the development of disorders in glucose and insulin metabolism
(1–7). Indeed, hyperprolactinemia has been related to the pathogenesis of impaired
glucose tolerance and hyperinsulinemia up to overt insulin resistance (8–14), as
demonstrated by the evidence that high PRL levels promote the increase of the surrogate
index of insulin resistance (HOMA-IR, 11–13) and the reduction ofthe surrogate index
ofinsulin sensitivity (14), either in obese and lean patients. PRL excess induces the
functional blockade ofdopaminergic tone, which in turn may be accounted among factors
implied in the pathogenesis of hyperphagia and weight gain seen in patients with
hyperprolactinemia, so contributing to obesity
• .(Auriemma et al., 2019)

19. • The dopamine agonists bromocriptine and cabergoline nowadays
represent the treatment of choice for patients with
hyperprolactinemia (24, 25). Interestingly, both drugs have been
demonstrated to significantly improve glucose profile in diabetic
patients independently on PRL status. In patients with prolactinomas,
bromocriptine has been found to significantly improve glucose
homeostasis and insulin resistance (17, 18, 36, 37), and to reduce
body weight
• (Auriemma et al., 2019)

20. • Interestingly, the overall effects of prolactin on metabolic health and
glucose homeostasis might vary depending on its circulatory
concentrations, as suggested by epidemiologic evidence. For example,
elevated prolactin levels above the normal range (i.e., hyperprolactinemia)
such as in the case of prolactinoma have been associated with adverse
outcomes including hyperinsulinemia (6), insulin resistance (6–8), and
increased body weight (9, 10). In contrast, higher prolactin levels within the
normal range have been linked to lower risks of diabetes in middle-aged,
non-pregnant populations (11, 12). As prolactin levels increase well-beyond
the normal non-pregnant levels during pregnancy, higher prolactin levels
during pregnancy might contribute to worsening glucose homeostasis
• Li et al found a significant and positive association of early pregnancy
prolactin levels with subsequent risk ofGDM.. (Li et al., 2020)

21. • Gestational diabetes is associated with adverse maternal, fetal and
neonatal outcomes. During pregnancy, the concentration of prolactin rises,
under the influence of elevated oestrogen and progesterone levels.
• Prolactin has been shown to have different effects on glu-cose metabolism
depending on the physiological state. High prolactin levels exacerbate
insulin resistance when elevated in a pathological context, such as in
patients with diabetes mellitus or with pituitary prolactinoma
• The association between serum prolactin and glucose might not be
revealed until the third trimester of pregnancy, as insulin resistance is most
prominent in the third trimester.

22. • Diabetes mellitus is classified into Type I DM, Type II DM, other types of DM, and
gestational diabetes.
• Diabetes mellitus in pregnancy is categorized into two, diabetes that has occurred
before pregnancy, pregestational diabetes and diabetes that occurs during
pregnancy,or gestational diabetes.
• Pregestational diabetes is found in pregnant women who have previously
suffered from type 1 or type 2 diabetes. All women with type 2 diabetes mellitus
who are planning to become pregnant are advised to seek counseling regarding
pregnancy in type 2 diabetes.
• Some references state that diabetes is diagnosed in the first trimester or early in
the second trimester. using the standard diagnostic criteria of hemoglobin A1C
(HbA1C) ≥ 6.5%, fasting plasma glucose ≥ 126 mg/dL, or 2-hour glucose of 200
≥mg/dL or greater on a 75-g oral glucose tolerance test, it is considered as
pregestational diabetes
(Caughey, Kaimal and Gabbe, 2018)

23. • Blood glucose targets in pregnant women with type 2 diabetes are:
• a) FBG 80 – 110 mg/dL;
• b) BG 1 hour post meal 100 – 155 mg/dL;
• c) HbA1c: < 7%; as normal as possible without the risk of frequent recurrence of
hypoglycemia.
• Severe hypoglycemia should be avoided.
• Patients are also advised to change oral anti-diabetic therapy to insulin, except for
metformin in cases of PCOS (polycystic ovary syndrome).
• Optimal target blood glucose control (without frequent hypoglycemia) (ADA 2015):
• Blood glucose before meals, at bedtime: 60 – 99 mg/dL
• Highest post-meal blood glucose: 100 – 129 mg/dL
• blood pressure targets in mothers with chronic hypertension are: Systolic 110 – 129
mmHg and Diastolic 65 – 79 mmHg (PERKENI, 2019)

24. • Insulin lispro and insulin aspart have better maternal glycemic control
benefits compared to soluble human insulin. The use of insulin lispro
or insulin aspart is associated with a decrease in peak glucose
concentrations, thereby reducing the risk of macrosomia in the fetus.
However, because there are very few data regarding the condition of
the fetus after birth, it is recommended that there is no need to
replace human insulin with short-acting insulin analogues. Especially
in female patients with T2DM or gestational diabetes where there is
little evidence of the benefits of insulin analogue replacement
(Wibisono et al., 2019)

25. • periodic blood glucose measurement in gestational diabetes is
recommended before breakfast (without calorie intake for 8-10
hours) and 1 hour or 2 hours after eating.
• In gestational diabetes, a pre-prandial blood glucose test is
sometimes necessary. In gestational diabetes and gestational
diabetes, the practical regimen should still be individualized (Kshanti et al.,
2019)