TOPIC: STANTARD GUIDELINES FOR

TREATMENT OF INFERTILITY DUE

TO HYPERPROLACTINEMIA

DISSCUSSANT: PHARM FAVOUR

IYAMU
MODERATOR: PHARM L. OKAFOR
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 INTRODUCTION
Human Prolactin (PRL) is a 198 amino acid polypeptide.
PRL is produced by the pituitary lactotrophs.
lactotrophs are similar in number in both sexes and do
not change significantly with age
Perhaps the most important classical role of prolactin is
to stimulate milk production in women after the delivery
of a baby
And to enhance breast development during pregnancy 2
 PRL cont’d…..

There are several other sources of PRL-like

substances in the periphery such as:
 placental lactogens (similar to pituitary PRL),

 mammary gland (produced within the mammary

epithelial cells),
 or PRL variants of immune cell origin (that
modulates the immune system) 3
 PRL cont’d…..

 Normal serum level is 10-25 ng/ml

 Less than 500 mIU/L [18 – 20 ng/mL] for women
Less than 450 mIU/L for men
Pregnant women: 80-400ng/ml

 Its half life is 20 minutes

 It is Metabolized in liver and kidney

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Hyperprolactinemia is higher-than-normal blood levels of
the hormone PRL.
 This hormone is made by the pituitary gland, which is
located at the base of the brain.
 High PRL levels are normal during pregnancy and
breastfeeding
 PRL can become too high because of a disease or the use
of certain medications. 5
 Hyperprolactinemia and Infertility

PRL is a pituitary-derived hormone that plays an

important role in a variety of reproductive functions.

High PRL levels interfere with the normal production of

other hormones, such as estrogen and progesterone

which can disrupt or stop ovulation, irregular periods.

It is relatively common in women than men, rarely

occurs in children 6
 Role OF PRL in Regulation of
Reproductive Function
PRL is essential to maintain regular estrus
cycles by stimulating ovarian production of
progesterone.
high PRL levels suppression of pituitary
hormones are associated with anovulation
PRL acts also directly on the ovary to inhibit
the hCG-induced follicle rupture, resulting in
the inhibition of ovulation.
NB: first signs in women with high PRL levels
may have irregular periods or no periods at all
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 EPIDEMIOLOGY
 Globally hyperprolactinemia occurs in less than 1%
of the general population and in 5-14% of patients
presenting with secondary amenorrhea.
 Approximately 75% of patients presenting with
galactorrhea and amenorrhea have
hyperprolactinemia.
 The most common type is a prolactin-secreting
tumor (Prolactinemia), which accounts for about
40% of all clinically recognized pituitary adenomas.

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EPIDEMIOLOGY Cont’d…
In UBTH…
 Clinical presentation in women is more
obvious and occurs earlier in men.
 A study carried out in the north eastern Nigeria
showed that hyperprolactinemia is a leading
cause of female infertility. Prevalence of
31.7% was reported. 9
 PATHOPHYSIOLOGY
The primary action of PRL is to stimulate the
increase of the epithelial cells of the breast and
induce milk production.
Estrogen stimulates the proliferation of pituitary
lactotroph cells resulting in an increased
quantity of these cells in premenopausal women,
especially during pregnancy.
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PATHOPHYSIOLOGY

During lactation and breastfeeding, ovulation

maybe suppressed due to the suppression of
gonadotropins by prolactin, but it may return
before menstruation resumes.
This however cannot be considered as a reliable
form of contraception
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 Prolactin secretion patterns Neuroendocrine
Regulation
 Secretion of PRL is under tonic inhibitory control by
dopamine, which acts via D2-type receptors located on
lactotrophs cells.
 PRL production can be stimulated by
 the hypothalamic peptides,

 vasoactive intestinal peptide (VIP),

 thyrotropin-releasing hormone (TRH) ,
 epidermal growth hormone

 and dopamine receptor antagonist. 12

PRL however inhibits the release of
gonadotropins releasing hormones (GnRH)
which is responsible for the stimulation of
 follicle stimulating hormone (FSH)
 and leutinizing hormone (LH)

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Regulation of Prolactin Secretion

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 Causes of Hyperprolactinemia
• Physiological conditions:
 Pregnancy  Sleep
 Puerperium  Feeding
 Nursing  Exercise
 Fetus  Coitus
 Neonate  Menstrual cycle
 Amniotic fluid

• If a woman's prolactin level is elevated the first time

it is tested, a second sample should be checked when
she is fasting and non-stressed.
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16
 Causes…
Pharmacologic Conditions
 Dopaminergic blockers; metoclopramide,
domperidone, norepinephrine
 Dopamine-depleting drugs: phenothiazine,
haloperidol, risperidone
 Opiates: cocaine, morphine, heroin
 Estrogens: oral contraceptives
 H2 blockers (ex cimetidine, ranitidine)

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18
 causes…
• Pathologic conditions
 Reflex causes
 Hypothalamic lesions
 Chest wall injury
 Craniopharyngioma
 herpes zoster neuritis
 Glioma
 Upper abdominal op
 Granuloma
 Hypothyroidism
 Stalk transection
 Renal failure
 Irradiation damage
 Ectopic production
 Pseudocysts
 Bronchogenic carcinoma
 Pituitary tumors
 Hypernephroma
 Cushing disease
 Acromegaly
 Prolactinoma
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Causes..

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 Idiopathic Hyperprolactinemia

NB: In many patients, elevated levels remain

unexplained and may represent a form of

hypothalamic pituitary dysregulation.

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 Hyper prolactinaemia Presentations

In Women
 Galactorrhea
 Disturbance of menstruation
In Men
 Hypogonadism
 infertility and
 erectile dysfunction

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Hyperprolactinemia Clinical Manifestation

Galactorrhea indicates elevated PRL in 10% of women and

99% of men.

Amenorrhea: indicates elevated PRL in 15% of women.

Galactorrhea plus amenorrhea: indicates elevated PRL in

75%of women.

Infertility: indicates elevated PRL in up to 33% of women.

Osteoporosis: increases with elevated PRL--due to estrogen

lack. 23
MEASUREMENT OF PRL

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 Hyperprolactinemia Mechanisms of
Reproductive Dysfunction
A. Inhibition of pulsatile GnRH secretion

B. Interference with gonadotropin action in ovary

C. Interference with estrogen positive feedback

D. Inhibition of FSH-directed ovarian aromatase

E. Inhibition of progesterone synthesis

F. Impaired follicle development

G. Inhibition of 5-alpha-reductase enzyme in men, thereby

decreasing the conversion of testosterone to DHT 25
 Hyperprolactinemia Interference with
gonadotropin action in ovary

• PRL can act as a potent inhibitor of LH-

mediated androgen synthesis and this will lead

to hypoestrogenemia .

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 Hyperprolactinemia Inhibition of
progesterone synthesis

PRL is involved in the induction of LH

receptors to maintain progesteron synthesis.
PRL is necessary for complete lutenization.

Hyperprolactinemia in the early phase of

follicular growth inhibit progesterone
secretion.
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Hyperprolactinemia and Impaired follicle
development
Follicular fluid obtained from mature follicles
contain lower PRL concentration
approximating those found in serum,
Highest PRL level occurs in the fluid of small
follicle, reaching 5-6 fold greater than those in
serum.
 If prolactin exceeds 100 ng/mL, 100% of the
follicles are atretic

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Hyperprolactinemia in Polycystic Ovaries

 PRL levels have been found to be elevated in

19- 50% of women with PCOS .
 The mechanism is still not firmly established,
but it may be the hyperestrogen levels that are
occurring in PCO.
 Cabergoline treatment of hyperprolactinemic
patients with PCO usually results in a reduction
of testosterone and LH levels and resumption of
ovulatory cycles.
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 Anterior Pituitary Masses and
Hyperprolactinemia
Pituitary adenomas (Prolactinomas)
Most common of functional pituitary adenomas
 25-30% of all pituitary adenomas
 Some growth hormone (GH)–producing tumors
also co-secrete PRL
Of women with prolactinomas - 90% present
with microprolactinomas
Of men with prolactinomas- up to 60% present
with macroprolactinomas
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31
Pituitary adenomas are often classified on the basis of size :
 Microadenomas < 10mm in diameter
 Macroadenomas > 10mm in diameter

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 Clinical Features of
Hyperprolactinemia/Prolactinoma

Women may present with oligomenorrhea,

amenorrhea, galactorrhea or infertility
Men often have less symptoms than women
(sexual dysfunction, visual problems, or
headache) and are diagnosed later
 In both sexes, tumor mass effects may cause
visual-field defects or headache 33
34
Management of Pituitary Adenoma

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Approach to diagnosis of hyperprolactinemia.

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 Investigations
Review the history ,physical examination, exclude the
physiological causes , drugs .
PRL level by radio immunoassay .

T.S.H. for assessment of thyroid function

X ray of the sella tursica to see any destruction by

macro adenoma of the pituitary gland
CT and MRI for the diagnosis of the pituitary tumor
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Treatment of hyperprolactinemia
 PRL levels can often be corrected by stopping suspected
medication
 Correction of hypothyroidism is also effective

 Dopamine agonists are treatment of choice for most

prolactinomas
 Choices include Bromocriptine, Pergolide and Cabergoline
Medical treatment is given to the subjects with microadenoma,
persistent postoperative hyperprolactinemia, and to those cases of

hyperprolactinemia when it is caused by other medications. 38

 Evaluation Of Drugs
DRUG CLASS MECHANISM OF DOSAGE INDICATION SIDE EFFECTS CONTRAINDICATI
ACTION ON

Bromocriptine A semi low dose at PRL Orthostatic Toxemia in

synthetic 1.25- 2.5 mg dependent hypotension, pregnancy,
ergot day; o 2.5 – menstrual nasal HTN
alkaloid, 10 mg per cycle congestion, postpartum &
dopamine day in disorder: nausea, in the
receptor divided doses infertility, vomiting, puerperium,
agonist amenorrhea, somnolence breastfeeding
inhibit PRL prolactinoma fatigue,
& lower psychic
blood disturbance
growth
hormone in
acromegaly

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 Evaluation..
DRUG CLASS MECHANISM OF DOSAGE INDICATION SIDE EFFECTS CONTRAINDICATI
ACTION ON

Cabergoline Dopamine 0.25 mg Inhibition of Hypotention, Postpaturm

receptor D2 twice weekly lactation dizziness, HTN,preecla
agonist , PRL soon after headache, msia,
inhibitor, delivery, nausea valvulopathy
antiparkison treatment of hallucination, pericardial
hyperprolacte drowsiness fibriosis
nemia
disorder

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 Objectives of treatment of
hyperprolactinemia
 Restoration and maintenance of normal gonadal function

 Restoration of normal fertility

 Prevention of osteoporosis

If a pituitary tumor is present:

 Correction of visual or neurological abnormalities

 Reduction or removal of tumor mass

 Preservation of normal pituitary function

 Prevention of progression of pituitary or hypothalamic disease

Therapy should be continued for up to 12 to 24 months depending on the

symptoms 41
 MAIN STAY OF
HYPERPROLACTENEMIA TREATMENT

• BEANS ET AL 42
Recommendations for resistant, malignant
prolactinoma
• ① A failure to achieve a normal prolactin level on maximum dose
• ② A failure to achieve a 50 % reduction in tumor size
• ③ A failure to restore fertility in patients
 the dose should be increased rather than referring the patient for surgery.
 Patients resistant to bromocriptine should be switched to cabergoline.
 TSA
 cannot tolerate high doses of cabergoline (11mg/week)

 who are not responsive to dopamine agonist therapy

 Radiotherapy
 who fail surgical treatment 43
 The role of the pharmacist
 Adequate supply of these drugs to the patient
 Counseling patients on drug dose and
administration.
 Educating patients on the expected side effect of
medication.
 Identifying, preventing and reporting drug related
problems.
 Ensuring good storage conditions of drugs.
 Educating other healthcare providers about the
dosage, side effects and contraindications 44
 Case Study
DEMOGRAPHY- Patient S.M is a 29 year old woman.

Esan by tribe, had never conceived and she resides in Benin

City.

FAMILY AND SOCIAL HISTORY- Patient S.M is a married

woman in a monogamous setting. She is a hair dresser by
profession and a Christian.

She doesn’t smoke and does not take alcohol. She was referred
for management of infertility
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 Case ….
CHIEF COMPLAINT:
patient S.M presented with galoctorrhea, disturbance
of menstruation and inability to conceive after several
coitus.

HISTORY OF PRESENT ILLNESS:

After menarche at age 12, menses occurred irregularly

for a year and then became regular. She initiated use of

oral contraceptive pills at the age of 22, then stopped at

age 27 to try to conceive. 46

 Case Study Cont’d
PAST MEDICAL HISTORY: a nulliparous female with histrory of
infrequent menstruation at menache
PAST MEDICATION HISTORY: long term use estrogen oral contrceptives
PHYSICAL EXAMINATION: Pleasant, middle-aged lady, nonafebrile,, not
dehydrated, galactorrhea
Vitals
 Temp 37.1°C (36.1-37.2)
 Weight 67.6 kg
 CVS: B.P- 110/70mmHg;
 RR- 14bpm. (12-16 BPM)
 PR 70BPM (60-100 BPM)
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 LABORATORY INVESTIGATION
PATIENT PRE LUTEAL FOLICULA MENOPAUS
VALUE OVULATOR VALUE R E
Y VALUE VALUE
FSH mIU/ml 2.4 6.3-24 1.5-7.0 2.9-12.0 17-95
LSH mIU/ml 0.8 9.6-80 0.2-6.5 1.5-8.0 8-33
PRL ng/ml 92.21 3-35 5-35 5-35 5-35

Progesterol 0.9 0.25-6.22 1.5-20.0 0.25-0.54 <0.41

ng/ml
Estradiol E2 75 93-575 43-214 18-147 <58
ng/ml

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• THYRIOD FUNTION TEST
• TSH- 3mU/ml (0.25-5)
• T3- 5pmol/L (4-8.3)
• T4- 12pmol/L (9-20)

• MRI
• 6-mm microadenoma.

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Case Study Cont’d

ASSESSMENT:
Infertility secondary to hyperprolactinemia

WORKING PLAN:
 Bromocriptine: start low dose at 1.25 mg day at night 14/7
 before increasing to 2.5 mg per day in divided doses 4/52

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CONSULTANT REVIEW
10:30HR

• Patient Seen
• poorly tolerated, with fatigue, nausea, and lightheadedness to the point of
syncopal events during her work as a hairdresser
• Imp: cannot tolerate medication
• Plan:
• Cabergoline 0.25mg twice weekly (Monday and Thursday) for 3months
• To be titrated upward based on tolerance

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DRUG THERAPY PROBLEMS
DRUG THERAPY YES/NO
PROBLEMS (DTPs)
UNECESSARY DRUG? NO
DOSAGE TOO HIGH? NO
WRONG DRUG? NO
DOSAGE TOO LOW? NO
INNAPROPRIATE yes
ADHERENCE?
ADVERSE DRUG actual
REACTION?
NEEDS ADDITIONAL DRUG NO
THERAPY?
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 DRUG THERAPY
PROBLEM
POTENTIAL /ACTUAL DRUG THERAPY
PROBLEM
 Adverse Drug Reaction

• BROMOCRIPTINE: with fatigue, nausea, and

lightheadedness to the point of syncopal events

• CARBEGOLINE: dizziness, lightheadedness,

weakness. BUT MORE TOLERATED

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 GOAL OF THERAPY
 To reduce human prolactin level to normal
 Reduction in tumor size
 Preservation of normal pituitary function
 Prevention of progression of pituitary or hypothalamic disease

 To restore normal menstrual cycle

 Restoration and maintenance of normal gonadal function
 Restoration of normal fertility

 To improve patient quality of life

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 PHARMACEUTICAL CARE
PLAN
• DRUG FOCUSED INTERVENTION
 Ensuring rationalize pharmacotherapy
 Drugs were adequately supplied to the patient on emergency.

 PATIENT FOCUSED INTERVENTION

 Patient was counselled on her health condition and adviced to
adhere to regular dosage regimen
 Patient was adviced to report any unfavorable drug reaction

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 PHARAMACEUTICAL CARE OUTCOME

CLINICAL OUTCOME-
 Patient’s prolactin leevel was reduced to 30–40ng/ml
 menses were sporadic and infrequent

HUMANISTIC OUTCOME
 she was never able to tolerate the medication sufficiently to attain
normal prolactin level
 She and her husband had not conceived despite regular unprotected
intercourse
ECONOMIC OUTCOME-
 the cost burden of the medication was also a factor
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 Conclusion

• Dopamine agonist have shown effectiveness in persistent

hyperprolactinemia, and reducing the symptoms of
amenorrhea/oligomenorrhea. At our institution patients with
symptomatic prolactinomas, both micro- and macroadenomas,
are treated with cabergoline as the firstline approach. In the
small group of patients who do not respond to this treatment, or
who refuse long-term therapy, surgery is offered. Radiotherapy
is given if both pharmacologic therapy and surgery fail.

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