Primary Ovarian Insufficiency

Reading: Committee Opinion 604

What is Primary Ovarian Insufficiency? 

1. Definition 

1. Depletion or dysfunction of ovarian follicles with cessation of menses before age 40 

2. Used to be caused premature menopause or primary ovarian failure 

3. Note: should not be confused with menopause because 5-10% of women with POI can still experience spontaneous conception and delivery 

What Causes POI? 

1. Causes of POI 

1. There are many, but usually caused by chromosomal abnormalities or damage from chemotherapy or radiation therapy  

2. Common cause: chemo and radiation 

1. Immediate loss of ovarian function after chemo/radiation is called acute ovarian failure 

2. Highest incidence occurs after use of alkylating agents or procarbazine 

3. Younger the patient at time of receiving chemo, the more likely some follicles will survive  

3. Common cause: premutation of the FMR1 gene for fragile X 

1. As a reminder, Fragile X is an X-linked dominant condition

2. Caused by an increase in the repeats of CGG, typically >200 

3. In fragile X, there is genetic anticipation, meaning that the number of repeats can increase as they get passed onto future generations 

4. A pre-mutation is when there is between 55-200 repeats, and those with Fragile X or a pre-mutation have a 20% chance of developing POI in their lifetime 

5. 1% of pre mutation carriers will experience final menses before age 18 

4. Another common cause: Turner Syndrome 

1. Chromosomal abnormality with XO instead of XX 

2. Certain people can also have Turner mosaicism, which can also lead to POI 

3. When evaluating adolescents with primary amenorrhea and no associated comorbidities, about 50% will have chromosomal abnormalities 

4. Can also lead to pubertal and growth delays 

5. Gonadal dysgenesis 

6. Less frequently can be caused by infection or infiltrative process 

7. Other cause could be iatrogenic (ie. removal of the ovaries) 

8. Can also have autoimmune component, as 4% of patients with POI will have adrenal or ovarian antibodies 

How do we diagnose primary ovarian insufficiency? 

1. Diagnosis 

1. Unfortunately, no consensus criteria to identify POI in adolescents, and so a delay in diagnosis is common 

2. Some adolescents may have hot flashes or vaginal dryness, but the most common presenting symptom is POI 

3. So in someone who is presenting with amenorrhea or menstrual irregularity for 3 or more months, important to evaluate for all etiologies (ie. pregnancy, PCOS, hypothalamic amenorrhea, thyroid abnormalities, hyperprolactinemia, and POI) 

2. Work up 

1. History and physical 

1. Ask about menstrual history, family history of early menopause, and other factors that may place patients at risk for POI (ie. above etiologies) 

2. Physical exam should include other signs of disorders of sexual development (ie. breast development, uterus present or absent) 

2. Labwork 

1. Obtain basal FSH and estradiol levels - do not obtain when patient is on OCPs or other hormonal medications 

2. Pregnancy test 

3. Thyroid function tests and prolactin 

3. If gonadotropins are elevated in menopausal range (FSH 30-40 mIU/L), a repeat FSH measure is indicated in 1 month

1. If FSH is still elevated, this is diagnosed as POI 

2. Hypoestrogenism is when estradiol levels are <50 pg/mL 

3. Once diagnosis is established 

1. Karyotype 

2. FMR1 pre mutation testing 

3. Adrenal antibodies 

4. Pelvic ultrasound  

5. Meeting with genetic counselor depending on genetic findings 

4. Other tests being studied  

1. AMH is currently being used to assess ovarian reserve, but should not be used to determine if someone is fertile or not 

2. Inhibin B is not recommended as there is significant variability between menstrual cycles 

Management 

1. Note about treatment 

1. Diagnosis can be emotionally distressing in young women 

2. Therefore, treatment should have focus on sensitivity to both physical and emotional needs 

3. Some patients may need referral to counseling/group therapy for support  

2. Goal overall physically is to replace the hormones that the ovary would be producing before age of menopause 

1. May need more than menopausal women 

2. Pubertal development 

1. Breast development 

1. Initiate estrogen and increase gradually before administering progesterone until breast development is complete to prevent tubular breast formation 

2. Consultation to REI or PAGs for further management 

3. Ongoing hormonal treatment 

1. Will be necessary to prevent comorbidities 

2. Usually, transdermal, oral, or occasionally transvaginal estradiol of doses of 100 mcg daily is the therapy of choice 

1. Remember that oral estradiol can be used, but there is a higher risk of VTE compared to transdermal estrogen 

3. Addition of progesterone for 10-12 days each month is protective against endometrial hyperplasia 

4. The instinct may be to reach for OCPs, but OCPs have a much higher dosage of estrogen than is needed, and so is not first line treatment 

3. Associated Comorbidities 

1. Bone loss 

1. We know that ovarian function loss can affect bone architecture, especially in adolescents when bone accrual is at its maximum 

2. There is no consensus regarding DEXA scan or monitoring bone density annually; some do, but the the implications of low bone mineral density result in this population is unclear given low risk of fracture 

3. Long term use of bisphophonates is not recommended because of uncertain adverse effects and safety profiles 

2. Cardiovascular Disease 

1. Those with early estrogen loss are at higher risk of CV mortality 

2. Other than supplementing estrogen, there should be monitoring 

3. Routine visits should also focus on other methods of prevent CV morbidity: smoking avoidance, appropriate diet and exercise 

4. Blood pressure measurement annually and lipid levels every 5 years 

3. Endocrine Disorders 

1. 20% of adults with idiopathic POI will experience hypothyroidism, commonly Hashimoto’s thyroiditis 

2. No formal recommendation, but appropriate to test for thyroid insufficiency every 1-2 years 

3. Test for adrenal antibodies and should undergo yearly corticotropin stimulation testing as there is a 50% chance of developing adrenal insufficiency 

4. Fertility and Contraception 

1. For patients that desire to start families, they should be referred to REI to discuss options 

1. Can have egg preservation if possible 

2. Can also discuss other ways of having offspring (ie. donor eggs, gestation carrier) 

2. Fertility can still persist as long as few follicles are present 

1. Therefore, contraception should still be a discussion 

2. OCPs can be prescribed, but other methods such as IUDs or barrier methods can also be used 

3. Even if estrogen method is not chosen, estrogen should still be supplemented for the above reasons 

4. A missed period should still warrant a pregnancy test 

Hysteroscopy II: Complications and Troubleshooting

Here’s the RoshReview Question of the Week!

A 45-year-old woman in the postoperative recovery unit develops dyspnea. Her serum sodium is 130 mEq/L. Which of the following was the most likely distending medium used during her hysteroscopic monopolar fibroid resection?

• 1.5% glycine

• 5% mannitol

• Lactated Ringer solution

• Normal saline

Check out the answer and enter the QE QBank Giveaway at the links above!

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Why do we do hysteroscopy?

• Diagnostic

  • AUB

  • Infertility

  • Structural anomalies

• Operative

  • IUD removal

  • Polyps

  • Fibroids

  • Septums

  • Intrauterine adhesions and Ashermans

  • Endometrial ablation

  • C/section scar (isthmocele) excision

  • C/section scar or cervical ectopics

  • Tubal cannulation

Complications of Hysteroscopy -check out ACOG CO 800!

• Perforation

  • Most common complication - range 0.12-1.61%

  • Risk factors

    • Blind insertion of instruments

    • Cervical stenosis

    • Anatomic distortion - fibroids, adhesions, myometrial thinning, extreme anteversion or retroversion)

  • High index of suspicion

  • Decrease risk by using ultrasound or laparoscopic guidance

  • With dilation or with scope (unlikely)

    • Low risk of subsequent complications

  • During instrumentation

    • Increased risk of injury to extra-uterine structures

    • Requires evaluation - laparoscopy +/- laparotomy 

• Fluid Overload

  • Rare - 0.2%

  • Risk factors - resection of large or deep lesions, high pressure setting

  • As reviewed in prior episode

    • Limit fluid deficit to 1000mL for electrolyte-free hypotonic media, 2500mL for electrolyte-rich isotonic media

    • Use fluid management systems, Designated individual to monitor fluid deficit, decreased deficit limits for patients with comorbidities

    • Other preventive measures

      • GnRH agonists (pre-op)

      • Intracervical vasopressin injection

      • Planning for staged procedures

  • Management

    • Stop procedure

    • Assess hemodynamic, neurologic, respiratory, CV status

    • Check labs - serum electrolytes, osmolality

    • Consider loop diuretic (Furosemide)

    • Consider hypertonic saline

• Hemorrhage

  • 0.03-0.61%

  • Risk factors - cervical laceration, uterine perforation, cavitary lesion resections

  • Management will depend on site and severity of bleeding

    • Suture, electrocautery, intrauterine foley balloon, UAE, hysterectomy

  • Prevention

    • Dilute vasopression injection

• Cervical laceration

  • Prevention

    • Ensure good bite with tenaculum

• Air embolism

  • 0.03-0.09%

  • Risk factors - repetitive reintroduction of instruments through the cervix, not purging air from tubing

  • Signs/symptoms

    • If awake - chest pain, SOB 

    • If under anesthesia - decreased end-tidal CO2, hypotension, tachycardia

    • Mill-wheel murmur on physical exam

  • Management

    • Terminate procedure - deflate cavity

    • Place patient in left lateral decubitus and trendelenburg to move air bubble away from RV outflow tract

• Infection

  • 0.01-1.42% (includes intrauterine infection (endometritis) and UTIs)

  • Risk is low enough that antibiotic prophylaxis not routinely warranted

• Vasovagal reaction

  • Typically due to cervical dilation

  • Stop procedure, assess ABCs, raise legs/Trendelenburg

  • Can consider atropine if needed for bradycardia

Troubleshooting Hystersocopy

• Cervical stenosis

  • Misoprostol (200-400mcg vaginally 12-24 hrs pre-procedure)

  • Vasopressin

  • Small dilators (lacrimal duct dilators), ultrasound guidance

• Sudden increase in fluid deficit

  • Consider perforation

  • Ensure all outflow is being collected appropriately

• Reaching fluid deficit limit

  • Staged procedures (particularly Type 2 fibroids)

Puberty and Precocious Puberty

Here’s the RoshReview Question of the Week!

A 30-year-old woman brings her 7-year-old daughter for consultation. She noted the presence of clinical signs of puberty and is worried that this might be occurring too early for her age. Which of the following distinguishes central precocious puberty from peripheral precocity?

• Adrenarche

• Basal luteinizing hormone

• Bone age

• Secondary sexual characteristics

Check your answer by clicking the links above!

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What is puberty? 

• Physical process of maturation from child to adult that is capable of sexual reproduction 

• Also process of cognitive and psychosocial maturation

• Two main areas: 

  • Gonadarche - activation of the gonads by pituitary hormones (FSH/LH) 

  • Adrenarche - increase in production of androgens in the adrenal cortex 

• Cause

  • Triggered by hypothalamic activation and production of GnRH in pulsatile fashion that leads to FSH and LH production 

  • Not completely understood what causes the hypothalamus to begin this process

    • Thought to be governed by many factors like general health, nutrition, genetic factors, and other environmental cues 

    • Interesting to think about since the age of menarche in Europe decreased from 17.5 to 12.5-13 years in the last few centuries 

• Timing of puberty

  • On average, girls begin puberty at age 10-11

• One other note 

  • Puberty can be a time of emotional distress 

  • Not only are patients usually preteens or teens, with multiple societal and home pressures (school, friends, parents, etc), they are also experiencing significant changes in their bodies 

  • Child psych studies have shown that clinical symptomatology for previously diagnosed psychiatric disorders increase steeply when they reach puberty, and for some, this is the first onset of psychological symptoms 

  • So for these patients, important to follow them and work closely with your peds colleagues 

What are the different components of puberty? 

Mnemonic: boobs, pubes, spurt, squirt - Defined by Marshall and Tanner in 1970 (yes, that Tanner!) 

• Thelarche - breast development 

  • Usually first physical sign of puberty is breast buds 

• Pubarche (adrenarche?) - growth of pubic hair, usually follows a few months after breast development begins 

  • Thelarche and pubarche form the basis for Tanner staging in girls: (image source)

• Growth spurt  

• Menarche - getting your first period; the average age in the US is around age 12

View fullsize

So what is precocious puberty? 

• More on timing of puberty:

  • Usually, puberty begins around the age of 10

    • However, there is a wide range, and can be anywhere from age of 8-13. Remember, puberty is NOT just beginning of menstruation! 

    • It can be evidence of breast development, pubic hair growth, etc.  

  • Precocious puberty is evidence of puberty that starts 2.5 SD earlier than the populational norm

    • Classically, it’s been defined as breast budding before the age of 8 in girls, though there is some racial differences in the literature that range somewhere between the ages of 7-8, and there is an increasing trend of earlier puberty in the US.

    • For simplicity’s sake, we will use the age of 8 as our cut off – at least when we should start THINKING that there maybe signs of precocious puberty 

• Incidence and Risks

  • This is a little difficult to assess 

    • You might expect it to be 2% because we are using 2 to 2.5 standard deviations from the general population in the US 

    • But… in a population-based study, breast and/or pubic hair development at age 8 occurred in 48% of Black females and 15% of white females in the US. At age 7, this was 27% and 7% 

    • But if you look at a different population, the results are drastically different 

    • So… definition of precocious puberty is overall problematic, especially in female children. Instead, need to take into other factors as well, such as obesity

• Strong predominance for females (approximately 87% of those evaluated in one study) 

• In about 80% of girls with precocious puberty, it will be idiopathic 

Why do we care about precocious puberty? 

•  Psychosocial reasons

  • Early menarche is often associated with earlier timing of sexual debut 

  • Increased risk of teenage pregnancy and sexually transmitted infections (HPV) 

  • Children may not be prepared for the implications of puberty and sexual maturation 

• Other implications/health 

  • Early closing of the epiphyseal plates can lead to shorter stature 

  • Increased risk of breast cancer, heart disease, diabetes, and all-cause mortality 

What causes precocious puberty? 

• Central precocious puberty (CPP)

  • Definition: Early maturation of the HPO axis … what causes it? 

  • Idiopathic 

    • In about 80-90% of females, but only 25% of males 

  • Central nervous system lesions

    • Hypothalamic hamartomas 

    • Other CNS tumors 

    • Cranial radiation 

• Peripheral precocity 

  • Usuall due to excess secretion of sex hormone 

  • Ovarian tumors - overall rare, but can be from granulosa cell tumors. Rarely, sertoli/Leydig cell tumors can cause androgenization 

  • Primary hypothyroidism 

    • Severe, long-standing hypothyroidism can occasional cause precocious puberty 

    • Thought is due to cross-reactivity and stimulation of FSH receptor by high levels of TSH (same alpha sub unit) 

  • Exogenous chemicals/sex steroids  

  • Adrenal tumors 

  • Congenital adrenal hyperplasia - though these patients may present as early as infancy 

  • McCune-Albright Syndrome

    • Super rare → triad of peripheral precocious puberty, irregular cafe-au-lait spots (coast of Maine), and fibrous dysplasia of the bone  

How do we work this up? 

• As always, history and physical 

  • If you suspect, you should ask patient and guardian 

  • When did they first notice changes, and how long has this been going on for? 

  • How quickly has this been progressing? 

    • Has this been occurring in the last year, and there has been very quick development of breast tissue with rapid onset of menstruation? More concern for peripheral source or tumor 

    • What about growth? Rapid growth may suggest CPP. Slower growth might signal benign or idiopathic cause 

  • Any changes with headaches, vision changes (suggests CNS tumor) 

  • Possible exposure to exogenous chemicals? Is mom on hormone replacement therapy and using estrace gel or cream? Did the child somehow get into it? 

  • Physical exam 

    • Height, weight, and height velocity (not something we usually do, so this might be best evaluated by the patient’s pediatrician!) 

    • Look for signs of McCune Albright - are there cafe au lait spots? 

    • Pubertal staging (Tanner Staging) 

• Testing to order 

  • Bone radiograph - we don’t generally do this, so maybe think of referring to pediatric endocrinology, especially for follow up

    • Usually a hand X-ray to look at the growth plates in the metacarpals, wrist, etc 

    • Can assess for advance in bone age or premature closure of the growth plates 

  • FSH, LH, estradiol, and testosterone 

    • Elevated estradiol with suppression of FSH or LH is suggestive of peripheral production 

  • Consider getting a brain MRI to r/o central lesion 

  • Pelvic ultrasound - this will allow us to see peripheral tumors 

  • Specifically in patients with precocious pubarche (ie. pubic hair growth, axillary hair growth, but no menarche) 

    • Measurement of adrenal steroids 

    • Early morning 17-OHP, DHEA, testosterone, androstenedione 

• Also refer to pediatric endocrinology! 

• Treatment is based off of the cause - which we won’t cover today, but:

  • Principles of treatment will be based off of child’s age, rate of progression, height velocity, estimated height 

  • Goal of treatment is to allow child to grow to normal adult height and also to relieve psychosocial stress 

  • Usually for children with CPP, can treat with GnRH agonist 

  • Again - usually this is done with pediatric endocrinology, so we will defer further management to them.

    • This episode is designed to help you figure out the initial stages if someone comes to you with this issue!

Hysteroscopy: The Basics, feat. Andrey Dolinko, MD

Today we’re joined for a first part of a two-part talk on hysteroscopy with special guest, Dr. Andrey Dolinko! Andrey was our co-resident at Brown and is currently a second-year fellow in reproductive endocrinology and infertility at the University of Pennsylvania.

What is hysteroscopy?

• Ancient Greek hustérā, “the womb” & Skopéō - to see 

• History (Rudic-Biljic-Erski et al 2019)

  • First developed in mid-19th century

    • Pantaleoni performed hysteroscopy on a 60yo woman to diagnose an endometrial polyp and treated it with silver nitrate. Used cystoscope developed by Desormeaux that used series of concave mirrors and light source

  • Early 20th century

    • Carbon dioxide used as first distention medium in 1925

    • 1926 - two-channel hysteroscopy (introduction and suction of distention media)

    • 1927 - operative channel introduced

    • 1928 - irrigation system

    • 1930s - fixed optic systems and fluid delivery systems

  • Second half of 20th century

    • Fiberoptic cable added to hysteroscope in 1965 (cold xenon light)

    • Operative hysteroscopy and use of different distention media takes off in 1970s

    • Videoendoscopy started in 1982

    • 1996 - Bettocchi office hysteroscope

    • 1990s - resectoscopes, first monopolar and then bipolar

  • 21st century

    • Morcellators - i.e., MyoSure

How does hysteroscopy work?

• Contraindications

  • Pregnancy

  • Cervicitis

  • Active PID

  • Comorbidities that may be exacerbated by intravascular volume expansion

• Timing

  • Reproductive-aged women: proliferative phase CD5-12, ideally not during active bleeding

  • Exclude pregnancy!

  • Post-menopausal-aged women: any time
    

• Positioning

  • Dorsal lithotomy position

  • Avoid steep trendelenburg because risk of air embolism

    • Causes negative pressure in pelvic veins

• Patient prep

  • Vaginal prep w/4% chlorhexidine gluconate soap or providone-iodine

• Antibiotics

  • not indicated

• Anesthesia (ranges)

  • None

  • Can do PO/IM/IV NSAIDs, benzos

  • Paracervical blocks

  • Regional anesthesia

  • IV sedation

  • General LMA

  • GETA

• Vaginal instruments

  • Speculums and retractors

  • Tenaculum

  • Dilators

  • Curettes

• Hysteroscope

  • Hysteroscope components

    • Scope

      • Eyepiece

      • Barrell

      • Objective lens

        • 0 to 70 degrees (typically 0 or 30)

    • Inner sheath w/inflow

    • Outer sheath w/outflow for operative scopes

    • Light source

      • Most-commonly Xenon or LED these days

    • Camera-head and video monitor

  • Diagnostic

    • Flexible

    • Rigid

  • Operative

    • Rigid operative scope

    • Scopes to be used with hysteroscopic tissue removal systems

    • Resectoscopes

  • Distention media

    • Fluid choice

      • Historical

        • Gas - CO2

        • High-viscosity 32% Dextra (Hyscon)

      • Current

        • Low viscosity

          • Electrolyte-rich

            • Saline

            • LR (rarely)

          • Electrolyte-poor

            • 5% Mannitol

            • 3% Sorbitol

            • 1.5% Glycine

    • Fluid deficit

      • A reflection of potnetial systemic fluid absorption

        • Surgical disruption of endometrium and myometrium provides direct access to sinus/vessels

          • If intrauterine pressure greater than vascular pressure → intravasation -> a fluid bolus!

      • Where else may the fluid be going?

        • Out the tubes

        • Out the vagina

        • Onto the floor

  • Fluid management systems help to determine deficit

    • Simple

      • Gravity

      • Pressure bag

    • Automated systems

      • Can set fluid deficits for automatic calculation

      • Uterine pressure setting

HCG with Dr. Vivienne Meljen

Today we welcome Dr. Vivienne Meljen, senior resident at Duke OB/GYN, to talk to us about one of her favorite topics — bHCG, the “pregnancy hormone.” There’s a lot to unpack — so these notes are broken down as our Q&A conversation!

What is hCG?  

• Human chorionic gonadotropin or hCG is part of a family of glycoprotein hormones including TSH, FSH, and LH.  

• These are hormones produced by the pituitary gland. hCG included!

• They are each heterodimers and have an alpha and a beta subunit.  The alpha subunits are identical and beta subunits are all a bit different 

  • In fact, luteinizing hormone (LH) and hCG are super similar and come from shared genes, so when LH is being made in large amounts, hCG is also made and may be elevated.  

• HCG is metabolized by the liver and kidneys.  

Where does hCG come from?  

• Traditionally we think of hCG as being produced by “a pregnancy”. The part of a pregnancy that makes hCG is the trophoblast - what will eventually become the placenta.  

• It also comes from the pituitary gland as we mentioned earlier. And some cancers can make hCG 

What does hCG do?  

• To understand what hCG does, we need to back track a bit and remember how a pregnancy starts.  

• To get to hCG production, there must be fertilization and then implantation of the pregnancy. This process of reaching implantation takes about 7 – 10 days as the embryo floats through the tube to its final implantation site.  

• Once it has implanted, the trophoblast makes hCG which then stimulates the corpus luteum to keep making progesterone, which helps continue to support gestation. At about 10-12 weeks, hCG levels usually peak and thereafter, the placenta takes over hCG production. 

  • This is apparent in patients’ thyroid testing. In normal pregnancy with an asymptomatic patient, TFTs could be slightly abnormal at this point due to the cross-reactivity and homology between TSH and hCG.  

So someone can be pregnant, but not necessarily have hCG? Is that right?  

• Yes, while that blastocyst is making its way to implantation, the corpus luteum is making its own progesterone and there is no hCG yet so a pregnancy test will be negative. In order to minimize variation in ability to detect a pregnancy, we should time pregnancy testing to be done at 15 days after LH surge, instead of testing at the time of expected menses.

  • This is why in contraception management if we cannot reasonably exclude pregnancy, we recheck in ~ 2 weeks because we would “capture” most pregnancies at that point. 

I know there is hCG, but I always hear about “betas” or “checking a beta”. What’s that about?  

• Like I mentioned, hCG is a heterodimer with an alpha and a beta subunit. Most people say “check a beta” meaning “check a quant”. The reference to betas is actually due to a misunderstanding back when the hCG immunoassays were first being created, and a bottle of antibodies was labeled as “beta subunit” and it was interpreted as the test only testing for beta subunits. In fact, most hCG tests are detecting all different types of hCG when you get a quant.   

What can we use hCG testing for?  

• Detecting pregnancy  

• Tumor marker monitoring in molar pregnancy and GTN  

• Screening for trisomies in pregnancy with quad screen for example  

What can we use hCG itself for?  

• One of the evidence-based and legitimate ways to use it is in the REI world for ovarian hyperstimulation for ART. HCG is the “trigger shot” to help mature eggs because it simulates an LH surge due to its homology.  

• Note- by the time you’d want to test for pregnancy in a woman undergoing ART, this should have cleared so it shouldn’t affect testing.  

What’s the normal rate of rise for hCG in a normal pregnancy?  

• We use serial hCG concentration measurements as a tool to help us differentiate normal from abnormal pregnancies 

• Back in the day, the rule of thumb was that hCG would rise ~51% every 48 hours.  

• Now we know that hCG rate of rise depends on the initial value with the % rise being greater at lower values. For an initial hCG level of < 1,500 the expected rate of rise is > 49% versus starting over 3,000 the expected rate of rise is in the ~33% range. Most normal pregnancies will rise faster than this.  

What about hCG levels going down?  

• While we have some clear guidelines about a 15+% decrease in hcg levels between days 4 and 7 following mtx administration for suspected ectopic pregnancy, it is less clear in other situations. 

• There is no specific rule, but per ACOG, following an SAB hCG levels should normalize within 2-6 weeks. This likely depends on the initial value.  

What can cause a positive pregnancy test?  

• Pregnancy (normal, abnormal, ectopic) 

• HCG doping (people use it for weight loss and for sports) 

• A slew of possible causes of false positives we will get into later  

What’s the deal with urine and serum testing for hCG?  

• Urine tests are QUALITATIVE – positive or negative  

• Most Serum tests are QUANTITATIVE – give you a number amount usually in IU/L 

• Urine tests will typically turn positive at the same point at which a serum test is > 20-25. However, you can have a false negative urine study if the urine is very dilute and a woman’s hCG level is low.  

• Most of these test employs antibodies that sandwich hCG when present and then are converted into a test result.  

• Because they use antibodies though, some other things can cause antibodies to link and create a false positive or negative result that you need to be aware of.  

• On a typical urine test or a “UPT” seeing 1 line is a sign that the control and test works, 2 lines means hCG is present.  

  • You can get a false negative test with a rare situation called the “hook effect” when you have SUCH a high level of hCG (think GTN levels) that the sandwich antibodies are saturated on both ends and can’t link together to give a signal.  

False positive tests seem to be fairly common and weird. Can you take us through those?

• Heterophile antibodies are often referred to as “phantom hCG”. These are nonspecific, low affinity antibodies that can crosslink the antibodies in the test and make it seem positive. 

• Where do these antibodies come from? - Some people at greater risk of these heterophile antibodies are people who have worked on a farm or in a veterinary facility, women with rheumatologic conditions, patients who have rec’d recombinant antibodies for medical treatment, some who have received plasma exchange from an unknowingly pregnant donor.  You can filter out for these by cross checking with urine that should be negative, trying a different assay, or having your lab perform serial dilutions or use a heterophile-blocking agent. 

• Pituitary hCG is often seen in perimenopause or post-chemotherapy. This makes sense because of the homology to LH. So when LH is high, hCG rises with it. You can suppress this by giving OCPs to see if it normalizes in a few weeks.  

• “Chemical pregnancy” is another potential “false” but not really false positive. This is an implanted conception that produces hCG but results in a SAB by the time of expected menses.  

• Familial hCG is a bizarre and rare cause where there is a hereditary cause of hCG production that can be present throughout ones entire life at low levels.  

• Kidney disease is one of the more common causes I’ve been called for and this is a tricky one. The exact mechanism for why patients with ESRD have false positive hCG is not known but we think its related to impaired renal clearance and increased gonadotropin levels. The tough part is that these patients often do NOT produce urine so they get serum testing which if positive, we can’t cross check with urine to see easily if it is a heterophile. Often, these patients are tested in the setting of prepping for transplant and sometimes, in the final stretch before going to the OR for a new kidney; so a positive test can really complicate things. To make matters worse, they often have complicated menstrual histories so it is very hard to cross check timing of a possible pregnancy. It’s estimated that approximately 1.5% of dialysis receiving reproductive-aged women conceive over ~2 years so it’s possible. Usually, using a good history one can work this out and often these patients have a series of low positive quants over the course of years to help support that it is a false positive test. Some authors suggest using a good old fashioned progesterone level to help clarify the situation, though it isn’t fool proof.