Ongoing Pelvic / Lower Abdominal Pain and a Negative Work-Up: What Next? image

Ongoing Pelvic / Lower Abdominal Pain and a Negative Work-Up: What Next?

Differential Diagnosis for Unexplained Pelvic/Abdominal Pain

Learning Objectives: Upon completion of this activity, participants should be better able to

  1. Discuss the important elements of the work-up for ongoing pelvic/abdominal pain
  2. Construct a comprehensive differential diagnosis that may include disorders beyond the more typical gynecologic and gastrointestinal conditions

The Case

  • 32 yo G2P0020, previous history of 2 SABs, regular menses, negative pregnancy test
  • Presents for evaluation and management of pelvic/abdominal pain 

Chief Complaint

  • Experiencing recurring episodes of pelvic/lower abdominal pain, 8/10 intensity for days at a time
    • Sometimes experiences dull, aching, nonradiating, 4/10 intensity prior more acute episodes  
    • Some relief with ibuprofen 600 mg every 6 hours 
  • Pain is sometimes increased with bowel movements, urination, intercourse during more acute episodes  
  • Has seen multiple specialists (Gyn/GU/GI) in the past
    • Ongoing problem, unresolved for at least 2 years
    • Has undergone laparoscopy but no diagnosis as of yet


The differential diagnosis of pelvic/ lower abdominal pain is extensive. Sometimes, the diagnosis is clear, but patients may present with ongoing pain, lasting several months in duration. Of particular concern is when such pain leads to functional disability, need for medical care and incomplete relief with prior medical and surgical therapies. Below, we provide key points to consider when performing the work-up as well as where to look next when a clear answer from the common differential list is not apparent.

Part 1: Evaluation


  • Identify
    • Whether pain is cyclical, constant, episodic
      • Use of a daily diary may aid in establishing temporality and relationship to menses 
    • Site of pain | Duration | Positional change
    • Association with bowel/bladder function  
    • Ethnicity may be important (see rare causes below)  
  • Review
    • Medical treatments | Surgeries 
    • Menstrual History | Pelvic infections  
  • Ask about
    • History of sexual or physical abuse
  • Vague abdominal symptoms can be associated with undiagnosed ovarian cancer and should not be dismissed 

Note: Watch for ‘Red Flag’ signs and symptoms which require immediate evaluation/referral 

  • Rectal bleeding
  • New bowel symptoms and age >50 
  • New pain after menopause 
  • Pelvic or abdominal mass  
  • Suicidal ideation 
  • Excessive and/or unintentional weight loss
  • Family history of inflammatory bowel disease or colorectal cancer 
  • Abnormal vaginal bleeding, especially >40 years and postmenopausal
  • Postcoital bleeding


General Musculoskeletal Exam 

  • Observe gait, pain on position change
    • Disorders of pelvic floor and hip muscles may present as pain on standing up or lying down 
  • Evaluate
    • Spine | Paraspinous muscles | Sacroiliac joints

Abdominal Exam

  • Examine and palpate abdomen, both standing and reclining to assess for
    • Hernia | Endometrioma | Muscular trigger points  
  • Myofascial tenderness
    • Carnett sign: Palpate in the presence of flexed abdominal wall muscles
      • Increased tenderness: Contribution from myofascial sources 
      • Decreased tenderness: Underlying visceral sources  
  • Standing position
    • Easier to detect hernias or rare abdominal wall endometrioma
  • Assess for pulsating masses and bruit

Pelvic Exam

  • Begin pelvic exam with cotton swab palpation of vulva/vestibule
    • Check for vulvar vestibular syndrome and vaginal trigger points (see ‘Related ObG Topics’ below)  
  • Palpate (using single digit) to evaluate pelvic floor for tension myalgia
    • Levator plate | Piriformis | Obturator muscles  
  • Palpate without abdominal hand (also initially single digit) to eliminate myofascial component
    • Cervix | Uterus | Adnexa | Bladder | Urethra  
    • Add back abdominal hand to assess size/shape/mobility 
  • Rectovaginal exam
    • Assess for endometriosis and rectal masses


  • STI screening
    • Offer to all sexually active women 
  • CBC and ESR
    • Consider if chronic PID/infection is a consideration 
  • CA-125
    • CA-125 may be elevated in women with deeply infiltrating endometriosis  
  • Urinalysis and culture
    • Further urogynecologic work-up may be required in the setting of bladder/ upper urinary symptomatology or clinical findings  


  • Transvaginal ultrasound
    • Can reliably identify ovarian endometriomas, fibroids, hydrosalpinges 
    • In skilled hands, can be as sensitive as MRI for adenomyosis  
  • Pelvic MRI
    • May be useful in diagnosing adenomyosis  
    • Can help ascertain / identify palpable nodules on pelvic and rectovaginal exam  
  • Consider lower endoscopic ultrasound to evaluate rectal endometriosis

Role of Laparoscopy  

  • Once considered the ‘first line’ gold standard
    • Evidence for immediate ‘first line’ investigation is lacking, and other investigations may be completed initially  
    • Will usually follow a complete nonsurgical work-up 
    • ‘Conscious pain mapping’ of the pelvis (‘microlaparoscopy’), under local anesthetic to identify what organs are generating pain has been reported but not widely adopted  
  • Laparoscopy is still an important procedure for documentation of peritoneal endometriosis and adhesions
    • Laparoscopy alone may underdiagnose endometriosis and biopsies of suspicious areas may be required  
  • Minimally invasive laparoscopic surgery has an important role in diagnosis and treatment
    • Among well trained-surgeons, can lead to relief of pain related to endometriosis, chronic TOA or hydrosalpinx among other disorders 

Part 2: Differential Diagnosis – Common Disorders

The following differential diagnosis list is not exhaustive, but represents disorders to consider in a woman with ongoing pain, a non-surgical abdomen, and negative pregnancy test


Endometriosis and/or Adenomyosis (see ‘Related ObG Topics’ below for clinical findings, evaluation and treatment of endometriosis) 

  • Symptoms
    • Do not correlate with extent of disease
    • Vary widely
    • May overlap with Irritable bowel syndrome (IBS) and interstitial cystitis  
  • Cyclical presentation and point tenderness associated with dyspareunia suggests the possibility of nodules in the cul-de-sac  

Adhesive Disease

  • Associated with dense, not fine adhesions  
  • Strong data on association remains limited  
  • History: Surgery for
    • PID | TOA | Endometriosis  
  • Physical: Uterus fixed in position on examination 
  • Imaging: Benign  

Residual Ovary Syndrome (Trapped Ovary Syndrome) 

  • Ovarian preservation or unilateral salpingo-oopherectomy in premenopausal patient following hysterectomy  
  • Ovary can become entrapped in adhesions or attached to other tissues, such as vaginal apex  

Ovarian Remnant  

  • Residual ovary present following oophorectomy  
  • Classic symptoms
    • Absence of vasomotor symptoms | Cyclic pain | Dyspareunia if attached to vaginal apex   

Pelvic Congestion 

  • History
    • Dull, aching pain, bilateral and exacerbated by  
    • Prolonged standing | Premenstrual pain | Postcoital pain  
  • Imaging: Enlarged pelvic veins >5mm 
  • “Renal Nutcracker syndrome”—compression of left renal vein between abdominal aorta and superior mesenteric artery
    • Rare cause of lower abdominal/pelvic pain with intermittent hematuria

Vaginal Apex Pain 

  • History
    • Commonly presents as dyspareunia following hysterectomy 
  • Physical
    • Use a cotton-tipped applicator to examine the cuff 
    • Look for focal pain in the fornix  
    • Temporary relief with apical local anesthesia  


Levator Pain 

  • Pain with sitting
    • Worsens over the day 
    • Associated with dyspareunia 
  • Patient may sit on one buttock 

Pelvic Floor Disorders

  • Look for trigger points using cotton tipped applicator and gentle digital examination
  • Pelvic organ prolapse may be present  

Iliopsoas Tenderness  

  • May become obvious during the observation of gait and movement as well as the physical exam findings 


Irritable Bowel Syndrome (IBS)   

  • Recurrent abdominal pain on average at least 1 day/week in the last 3 months, associated with two or more of the following criteria
    • Related to defecation
    • Associated with a  change in the frequency of stool
    • Associated with a change in the form (appearance) of stool
  • Criteria should be fulfilled for the last 3 months with symptom onset  ≥6 months prior to diagnosis
  • Symptoms alone may be used to diagnose IBS per Rome IV criteria
    • Depending on other GI symptoms, a few more tests may be ordered such as CRP if suspicion for inflammatory bowel disease
  • Abdominal bloating/rectal mucous are suggestive of but not diagnostic of IBS  
  • Note: Deep infiltrating rectovaginal endometriosis may cause similar presentation 

Chronic Appendicitis  

  • Usually acute in presentation with peritoneal findings 
  • In some patients, may have intermittent pain with normal CBC 
  • Debate as to whether this is a true clinical rather than histological diagnosis 


  • Usually asymptomatic until incarceration occurs  

Diverticular Disease

  • Diverticulosis
    • Presence of diverticula (abnormal outpouchings of the large intestine) without inflammation
    • Precedes diverticulitis | Approximately 5% to 10% of patients with diverticulosis may develop acute diverticulitis
  • Acute colonic diverticulitis
    • Inflammation of diverticula
    • Risk increases with age
  • Typically localized pain but may in minority of cases presentation can be complicated (e.g., abscess, obstruction, bleeding, or perforation)
  • Treatment: Can be managed with bowel rest, antibiotics and fluids as outpatient if uncomplicated  

Abdominal Migraine

  • May occur in adults
  • Unpredictable paroxysms of abdominal pain associated with
    • Nausea/Vomiting | Headache | Photophobia | Palor
  • No other explanation
    • Case reports, based on a diagnosis of exclusion
  • May be relieved with pregnancy
  • Female/Male ratio is 9:1 with average age of 31
  • May not always be associated with headache
  • Treatment: Patients respond well to NSAIDs, antiemetics and possibly sumatriptan

Other GI Disorders to Consider 

  • Infectious causes
    • Signs/symptoms of GI infection, some of which may appear in the red flag section above
  • Vasculitis syndromes
    • Reason for abdominal pain in Systemic Lupus Erythematosus (SLE)


Interstitial Cystitis 

  • Can be either a primary cause, a component, or a secondary effect of chronic pelvic pain 
  • Typical history of multiple suspected/treated UTIs, negative cultures 

Psychosocial Issues

  • Psychological and social issues may occur in association with chronic pelvic and abdominal pain 
  • It may be difficult to determine causality
    • Depression and sleep disorders may be a result rather than a cause 
    • Nevertheless, proper management and treatment may improve quality of life   
  • Referral to mental health professionals can be beneficial for both diagnosis and management depending on the clinical scenario   

Part 3: Additional Diagnoses Following Typical Evaluation With Negative Results

  • Above patient received thorough history and physical
    • No findings on blood work and urinalysis 
    • Review of previous imaging, endoscopy and laparoscopy notes did not reveal any pathology
    • What next?

 Time to Consider Genetic Syndromes? 

  • Some patients will reach a point where they have undergone multiple evaluations
  • Genetic disorders associated with abdominal pain may not have been considered
  • While these disorders are rare or unusual, the typical presentation may fit the present scenario of a thorough work-up by multiple specialists, but no clear diagnosis
    • Female (especially for the autosomal dominant disorders below)
    • Multiple treatments including surgeries without improvement
    • Ongoing pain but no diagnosis, sometimes for several years

Below are a few genetic syndromes that could be placed on the differential 

Acute Intermittent Porphyria (AIP)

  • Autosomal dominant inheritance (low penetrance so may not a have an obvious family history)
    • More commonly seen in women  
    • Drugs (e.g. barbiturates, sulfonamides), alcohol, infection, stress, starvation, and hormonal changes can precipitate attacks  
    • Can be managed by specialists
      • Most individuals without the mutation will be asymptomatic
      • There is an association with hepatocellular carcinoma  
  • The HBMS gene, which codes for the enzyme hydroxymethylbilane synthase (also known as PBG-D) is only 50% functional
    • PBG-D is in the heme synthesis pathway and therefore a defect in the enzyme can lead to build up and release of precursors from the liver
      • 5-aminolevulinic acid (ALA): A neurotoxin and appears to cause clinical findings and complications 
      • Porphobilinogen (PBG): Primary precursor measured in urine for diagnostic testing


  • Suspect AIP in the following
    • Abdominal pain which may be severe (usually lasting 2 weeks)  
    • No peritoneal signs  
    • Patients may complain of pain in thighs  
    • Commonly associated with
      • Nausea & Vomiting | Hypertension | Tachycardia 
  • Other less common findings
    • Neurologic
      • Mental status changes (up to 30%): Depression | Psychosis | Anxiety |  
      • CNS: Seizures | Peripheral neuropathies |Weakness  
    • Lung function
      • Respiratory paralysis 
    • Genitourinary – bladder
      • Retention 
      • Dysuria  
      • Incontinence  
      • Sometimes urine will be red/brown urine  
    • Laboratory changes such as hyponatremia  


  • Increased urinary concentration of PGB (primary test) and  ALA
    • Most likely to be positive during or following a painful attack
  • Consider urine test or referral to genetics center for work-up and testing
    • Molecular testing is also available to detect the pathogenic variant (important for family studies)  
  • Other types of porphyria: Hereditary coproporphyria (HCP) and variegate porphyria (VP)
    • Both present with the similar abdominal pain, but patients may also exhibit skin lesions when exposed to sunlight

Familial Mediterranean Fever 

  • Autosomal recessive inheritance pattern
    • This disorder can be found on many of the expanded prenatal genetic carrier screening panels  
    • Relatively common in populations from the Mediterranean region
      • Armenian, Arab, Turkish, or Jewish ancestry 
    • Usually manifests in childhood or teenage years, but may appear much later in life  
    • Can be managed by specialists and while individuals may be asymptomatic between attacks, there is an association with amyloidosis leading to renal disease  
  • MEFV reduces the activity of the pyrin protein, that is important in the regulation of inflammatory processes
    • Both copies of the MEFV gene will have pathogenic mutations  
    • A prolonged, inappropriate inflammatory response leads to abdominal pain, serositis and related findings  


  • Recurrent episodes of pain
    • Abdomen 
    • Chest 
    • Joints  

Note: Pain episodes can last hours to days, and vary in frequency  

  • Other target areas
    • CVS
      • Pericarditis  
    • GU
      • Nephrotic syndrome 
      • Renal amyloidosis  
      • Renal failure  
  • Lab values
    • WBC >30,000/mL  
    • Elevated ESR  
  • In addition, the following may be present
    • Fever (common) 
    • Rash (erysipelas-like erythema) 
    • Headache 
    • ‘Prodrome’: Uncomfortable, mild abdominal discomfort or sensations in other target areas   


  • There are scoring systems based on clinical major and minor findings 
  • Molecular testing confirms pathogenic mutations in both copies of the MEFV gene  

Hereditary Angioedema

  • Autosomal dominant inheritance
    • Disorder that is associated with severe swelling (angioedema) of multiple systems
      • GI swelling results in abdominal pain  
      • May be associated with other autoimmune disorders  
      • Mostly seen in women  
    • Associated with triggers (e.g. trauma, anxiety, stress) but often no obvious factor is identified  
    • Usually presents in childhood with worsening following puberty but may occur later in life  
    • Can be managed by specialists, which is important considering due risk for laryngeal swelling and airway obstruction
      • New drugs are being studied to prevent and manage this disorder  
  • Mutations in the SERPING1 gene cause type I and type II
    • SERPING1 regulates C1-inhibitor protein which controls inflammation  
    • Pathogenic variants cause C1-inhibitor deficiency and corresponding inappropriate inflammatory responses  
    • Excessive bradykinin protein fragments cause fluid leakage through blood vessel walls 
  • Mutations in the F12 gene cause some cases of type III
    • F12 regulates coagulation factor XII that plays a role in clotting and the bradykinin protein  
    • Pathogenic variants in F12 cause increased activity in factor XII and increased bradykinin  


  • Recurrent episodes of severe swelling (angioedema) with the following target areas
    • GI
      • Abdominal pain 
      • Vomiting  
      • Diarrhea  
      • Intestinal edema 
    • Limbs 
    • Face 
    • Airway
      • Laryngeal/Pharyngeal swelling  
    • Skin
      • Rash: Erythema marginatum (non-itchy)  
    • Neurologic
      • Peripheral neuropathy 
      • Impaired sensation  
  • Prodrome (occurs 50% of the time)
    • Local discomfort | Erythema marginatum | Fatigue | Muscle aches  

Note: Pain episodes can last for days but frequency and duration are variable


  • C4 levels: Mostly decreased  
  • C1-Inh activity: reduced  
  • Molecular testing to confirm pathogenic variant in a copy of the specific gene

The Wrap Up

  • Despite best efforts, some patients are left without a clear diagnosis but with ongoing pain  
  • Goal of treatment may be to ameliorate and better understand symptoms rather than make the patient completely pain free
    • Important for the patient and clinician to be aligned regarding aim of diagnosis and treatment plan
  • It is not always easy to distinguish between pelvic vs abdominal pain, especially in the lower quadrants  
  • Genetic causes, while rare, warrant consideration
    • Diagnosis often takes years or decades 
    • Presentation often involves multiple prior surgeries  
    • AIP and hereditary angioedema generally affect women
    • Ask patients about some of the associated symptoms, such as swelling for angioedema or weakness and/or neuropathies for AIP   
  • Refer to genetic specialists if unsure of the diagnosis
    • All clinical features are generally not present, and diagnosis may not be clear cut 
    • A detailed family history and genetic targeted history and physical may elucidate an underlying genetic disorder  
    • Screening tests can be ordered by non-genetic professionals, but if unsure, a genetic consultation can provide an avenue for appropriate testing  

Learn More – Primary Sources:

ACOG Practice Bulletin Summary 218: Chronic Pelvic Pain

Chronic Pelvic Pain (Obstetrics & Gynecology, 2014)

RCOG Green-top Guideline: The Initial Management of Chronic Pelvic Pain.  (reviewed 2017) 

Rome Criteria and a Diagnostic Approach to Irritable Bowel Syndrome (Journal of Clinical Medicine, 2017)

Abdominal migraine in the differential diagnosis of acute abdominal pain (American Journal of Emergency Medicine, 2015) 

Evidence-Based Medicine Approach to Abdominal Pain (Emergency Medicine Clinics of North America, 2016)

AAFP: Abdominal Aortic Aneurysm

GeneReviews: Acute Intermittent Porphyria 

GHR: Familial Mediterranean Fever

GeneReviews: Familial Mediterranean Fever

Emerging Therapies in Hereditary Angioedema (Immunology and Allergy Clinics of North America, 2017)

Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment (Annals of Medicine, 2016)

Diagnosis and Management of Acute Left-Sided Colonic Diverticulitis: A Clinical Guideline From the American College of Physicians | Annals of Internal Medicine (

AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review

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