Prolactinoma: Early Detection, Evaluation and Management

CLINICAL ACTIONS:

Prolactinomas are generally benign prolactin-secreting tumors and account for 40-66% of all pituitary adenomas.  The vast majority are microadenomas (diameter < 1cm) and suppress the hypothalamic-pituitary gonadal hormonal axis, while 10% are macroadenomas (≥ 1cm) and may cause additional mass effects due to size. Age prevalence varies widely, but they are commonly found in women during childbearing years, in part due to development of menstrual irregularities. Despite their benign nature, if diagnosis is delayed bone loss and vertebral fractures can occur, and the loss of bone density can be permanent.

Clinical signs and symptoms: 

• Oligo or amenorrhea
• Galactorrhea and gynecomastia
• Loss of libido and erectile dysfunction 
• Infertility
• Decreased bone density
• Mass effect:
  • Headache
  • Visual field abnormalities

Evaluation:

• Endocrine Society practice guideline
  • “To establish the diagnosis of hyperprolactinemia, we recommend a single measurement of serum prolactin; a level above the upper limit of normal confirms the diagnosis as long as the serum sample was obtained without excessive venipuncture stress” 
• History should be obtained to rule out obvious causes of elevated prolactin such as medications 
• MRI pituitary with and without contrast to assess size and type of tumor
• Prolactin levels
  • Prolactin levels above 200 µg/L is usually a prolactinoma
  • Prolactin levels above 500 µg/L likely indicates a macroprolactinoma
  • Prolactin macroadenomas can present with a falsely normal prolactin level due to the “hook effect” (false negative levels if excessive amount of analyte is present) 
  • When prolactin values are lower than expected in a patient, consider discussion with endocrinologist or clinical pathologist for further guidance
• Non-prolactin secreting pituitary adenomas can cause pituitary stalk or hypothalamus compression and consequent prolactinemia 
• TSH, free thyroxine (FT4), and creatinine levels to exclude secondary causes 

Treatment:

• Minimal symptoms (mild galactorrhea and normal menses): observation and monitor q6-12 months may be acceptable
• Oligo or amenorrhea (pregnancy not desired): oral contraceptives or other estrogen/progesterone combinations
• Most patients placed on dopamine agonists
  • Cabergoline > bromocriptine in reducing prolactin levels
  • Nearly 80% of patients treated with dopamine agonists will normalize prolactin level and reduce the size of their adenoma 
• Transsphenoidal surgery
  • Can result in normal prolactin levels in majority of microadenomas and up to 40% in macroadenomas
  • Recommended: When dopamine agonists not tolerated/desired | Acute tumor complications |Visual deficits not corrected with medical therapy 
  • Recurrence is possible (20% over 10 years)
• Radiotherapy
  • Rarely used for those cases that do not respond to the above
• Chemotherapy
  • Temozolamide rarely used with limited success
• Follow Up
  • Once prolactin levels have improved monitoring is recommended with repeat prolactin levels every 3 to 6 months for the first year and then every 6 to 12 months thereafter 
  • MRI should be repeated in 1 year for microadenomas or 3 months for macroadenomas after medical therapy is initiated 
  • Therapy may be tapered after 2 years of treatment for patients with normal prolactin levels and no visible tumor on MRI 
  • Recurrence rates after stopping dopamine agonists is between 26 to 69% and most likely to occur in the first year, and should be monitored with serial prolactin measurements every 3 months for the first year and annually thereafter 

SYNOPSIS:

The prevalence of prolactinomas is reported to be between 35 to 50 per 100,000.  They are most commonly seen in women (10:1 ratio female/male) and the usual age range is between 20 to 50 years of age. Dopamine originating in hypothalamic neurons is a principal inhibitory regulator of prolactin release by pituitary lactotrophs and this pathway is the basis of medical treatments.  Fortunately, only a minority of microadenomas will continue to grow (< 10%) but early detection, monitoring and a management plan, which may be multidisciplinary, is required for good outcomes. Consider accessing expertise in endocrinology and radiology to ensure correct differential between prolactinoma and non-secreting pituitary adenoma as treatment for the latter is usually surgical, not medical.

KEY POINTS:

Severe adverse effects of dopamine inhibitors are unusual but cabergoline may include compulsive behavior (e.g. excessive gambling) as well as cardiac valvular abnormalities at high doses

• Other causes of hyperprolactinemia include
  • Pituitary disorders (e.g. Cushing disease)
  • Hypothalamic disorders (e.g. non-secreting pituitary adenoma)
  • Neurogenic (e.g. chest wall or spinal cord lesions)
  • Medical
    • Hypothyroidism
    • Chronic kidney disease
    • Cirrhosis
  • Medications
    • Antipsychotics (e.g. phenothiazines)
    • Antidepressants (e.g. tricyclics, MAOIs, SSRIs)
    • Antihypertensives (e.g. verapamil, labetolol)
    • Anticonvulsants (e.g. phenytoin)
    • Prokinetics (e.g. metoclopramide)
    • Hormones (e.g. estrogen)
    • H2 blockers (e.g. cimetidine, ranitidine)
    • Controlled substances (e.g. opiates, cocaine, marijuana)
    • Other (e.g. alcohol)

Learn More – Primary Sources:

Orphanet J Rare Disease: The risks of overlooking the diagnosis of secreting pituitary adenomas

Diagnosis and Treatment of Pituitary Adenomas: A Review

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas 

Diagnosis and Treatment of Hyperprolactinemia: An Endocrine Society Clinical Practice Guideline 

Prolactinoma Management 

The epidemiology, diagnosis and treatment of Prolactinomas: The old and the new 

Underappreciation of the “Hook Effect” leading to Mismanagement of a Patient, a Tale of Preventable Disaster 

HPV Vaccine Recommendations Including Guidance for Ages 27 to 45

SUMMARY:

The most recent evidence-based HPV vaccine recommendations address when to administer the vaccine and dosing.  One area that has elicited more recent guidance focuses on whether to offer the HPV vaccine to individuals over the age of 26.

• The FDA (October 2018) extended approval of HPV vaccine to individuals age 27-45 years
• ACIP (June 2019) voted to
  • Expand routine and catch-up HPV vaccination in males through 26 years of age who are inadequately vaccinated
  • Offer HPV vaccine to individuals age 27-45 years who have not been adequately vaccinated based on shared clinical decision making
• ACIP published their final recommendations (August 2019) in the CDC’s Morbidity and Mortality Weekly Report

Children and adults aged 9 through 26 years: HPV vaccination is routinely recommended at age 11 or 12 years; vaccination can be given starting at age 9 years. Catch-up HPV vaccination is recommended for all persons through age 26 years who are not adequately vaccinated.

Adults aged >26 years: Catch-up HPV vaccination is not recommended for all adults aged >26 years. Instead, shared clinical decision-making regarding HPV vaccination is recommended for some adults aged 27 through 45 years who are not adequately vaccinated. HPV vaccines are not licensed for use in adults aged >45 years.

These recommendations for children and adults aged 9 through 26 years and for adults aged >26 years apply to all persons, regardless of behavioral or medical risk factors for HPV infection or disease.

For persons who are pregnant, HPV vaccination should be delayed until after pregnancy; however, pregnancy testing is not needed before vaccination.

Persons who are breastfeeding or lactating can receive HPV vaccine. Recommendations regarding HPV vaccination during pregnancy or lactation have not changed.

• ACIP suggests considering the following points for shared-decision making with adults who are 27 to 45 years of age
  • HPV is very common, usually transient and asymptomatic
  • Although typically acquired in young adulthood, some adults are at risk for acquiring new HPV infection
  • A new sex partner is a risk factor, while those in long-term, mutually monogamous partnerships are not likely to acquire a new HPV infection
  • HPV types: Sexually active adults will likely have been exposed to some HPV types, but not all HPV types are vaccine targets
  • There is no antibody test to determine immunity
  • HPV vaccine has high efficacy in young persons not yet exposed to vaccine-type HPV
  • Lower vaccine effectiveness may be expected in those with HPV risk factors
    • Multiple lifetime sex partners | Previous infection with vaccine-type HPV | immunocompromising conditions
  • HPV vaccines are prophylactic only and can’t prevent infection progression, improve time to clearance or treat HPV-related disease
• In summary, the CDC states

For adults aged 27 years and older, clinicians can consider discussing HPV vaccination with people who are most likely to benefit. HPV vaccination does not need to be discussed with most  adults over age 26 years

Updated ACOG HPV vaccine recommendations 

• Routine HPV vaccination is recommended for females and males 
• Target age is 11-12 years but can be given through age 26
  • Can be given from age of 9 
• Do not test for HPV DNA prior to vaccination
  • Vaccinate even if patient was tested and is HPV DNA positive
•  If not vaccinated between 11-12 years
  • Vaccinate between 13–26 years (catch up period)
• Women 27–45 years and not previously unvaccinated
  • Use shared clinical decision making
• ACOG “does not recommend that an individual who received the quadrivalent HPV vaccine be revaccinated with 9-valent HPV vaccine, including those aged 27–45 years who previously completed some, but not all, of the vaccine series when they were younger”
• Pregnancy
  • HPV vaccine is not recommended during pregnancy
  • Pregnancy testing prior to HPV vaccination not recommended
  • If vaccination schedule is interrupted by pregnancy, resume postpartum with the next dose
  • HPV vaccine can and should be given to breastfeeding women ≤ 26 who have not been vaccinated
• Counsel to expect mild local discomfort and that this is not a cause for concern
  • Watch adolescents for at least 15 minutes following vaccination due to risk of fainting in this population

AAP HPV Vaccine Implementation Guidance 2017

• The AAP  has also endorsed the CDC HPV recommendations and provides the following guidance

The AAP and the ACIP of the CDC recommend HPV vaccination with any available vaccine for routine immunization of females at 11 or 12 years of age, and recommend either 9vHPV or 4vHPV** for routine immunization of males 11 or 12 years of age. The vaccination series can be started as young as 9 years of age, and in the case of a child who has been the victim of sexual abuse, HPV vaccination is recommended beginning at 9 years of age.

AAP recommends that physicians frame their HPV discussions with families as an opportunity to prevent HPV-related cancer deaths rather than as an STI vaccine

ACS

• The ACS endorses ACIP CDC guidance regarding HPV guidance except for the approach to take with individuals who are 27 to 45 years and not adequately vaccinated

The ACS does not endorse the 2019 Advisory Committee on Immunization Practices recommendation for shared clinical decision making for some adults aged 27 through 45 years who are not adequately vaccinated because of the low effectiveness and low cancer prevention potential of vaccination in this age group, the burden of decision making on patients and clinicians, and the lack of sufficient guidance on the selection of individuals who might benefit

Learn More – Primary Sources:

FDA approves expanded use of Gardasil 9 to include individuals 27 through 45 years old

Human Papillomavirus Vaccination for Adults: Updated Recommendations of the Advisory Committee on Immunization Practices (MMWR)

CDC: HPV Vaccination Schedules & Recommendations

ACOG Committee Opinion 809: Human Papillomavirus Vaccination

CDC Frequently Asked Questions about HPV Vaccine Safety

CDC HPV Vaccine Fact Sheet for Parents

Human papillomavirus vaccination 2020 guideline update: American Cancer Society guideline adaptation

How to Tell the Difference Between the Flu and a Cold?

SUMMARY:  

The CDC provides information on how to discriminate between the flu and the ‘common cold’. Both conditions are viral in origin. Co-infection with bacteria is possible and in the case of infection with influenza virus, can lead to significant and serious complications.  

‘Signs and Symptoms’ Comparisons

	Influenza	Cold
Symptom onset	Abrupt	Gradual
Fever	Usual	Rare
Aches	Usual	Slight
Chills	Fairly common	Uncommon
Fatigue, weakness	Usual	Sometimes
Sneezing	Sometimes	Common
Stuffy nose	Sometimes	Common
Sore throat	Sometimes	Common
Chest discomfort, cough	Common	Mild to moderate
Headache	Common	Rare

Credit: Centers for Disease Control and Prevention

KEY POINTS:  

Flu Symptoms  

Patient may experience just a few or many 

• Fever or feeling feverish/chills 
• Cough 
• Sore throat 
• Runny or stuffy nose 
• Muscle or body aches 
• Headaches 
• Fatigue (tiredness) 
• Some people may have vomiting and diarrhea, though this is more common in children than adults

Note: Not everyone with flu will have a fever

Flu Complications 

• Moderate complications
  • Sinus and ear infections  
• Serious flu complications (can result from either influenza virus infection alone or from co-infection of flu virus and bacteria)
  • Pneumonia 
  • Heart inflammation (myocarditis) 
  • Brain inflammation (encephalitis)  
  • Muscle inflammation (myositis, rhabdomyolysis)  
  • Multi-organ failure (e.g., respiratory and kidney failure) 
  • Sepsis 
  • Exacerbation of chronic medical problems
    • Asthma attacks  
    • Worsening of heart disease  

High Risk Categories  

The following are at high risk of complications related to influenza virus infection 

• Young children 
• Adults aged 65 years and older  
• Pregnant women are at especially high risk 

Note: To see the comprehensive list of high risk flu categories (and more), see the CDC Emergency Advisory below in the ‘Related ObG Topics’ section

Learn More – Primary Sources:  

CDC: What is the difference between a cold and the flu?

CDC: Information for Health Professionals