von Willebrand's Disease, feat. Dr. David Abel

Today we welcome Dr. David Abel, Assistant Professor in obstetrics and gynecology at the Oregon Health and Sciences University. Dr. Abel’s expertise and interest is in the most commonly encountered bleeding disorder for OB/GYNs: von Willebrand disease.

You can join the Foundation for Women and Girls' with Blood Disorders as a student, resident, or fellow for FREE and get access to their educational content by visiting this link.

Some light reading to accompany today’s podcast:

• ACOG CO 580

• American Society of Hematology (ASH) guidelines on VWD

• VWD Review written by Andra James, MD, an MFM at Duke and Dr. Abel’s mentor

What is von Willebrand’s disease?

• First described in 1926 by Erik von Willebrand, a Finnish pediatrician.

• Most common inherited bleeding disorder, accounting for about 80 to 85% of all bleeding disorders.

• Prevalence about 1 in 10,000, though possibly as high as 1 to 2% of the general population.

  • With respect to women with heavy menstrual bleeding, the prevalence appears be greater, ranging from 5 to 24%. 

• Von Willebrand Factor is a large glycoprotein encoded by a gene on chromosome 12 that is synthesized in endothelial cells and megakaryocytes, the hematopoietic cells that produces platelets.

  • It is assembled from identical subunits into strings of subunits that vary in size and are referred to as multimers.

  • Two main functions:

    • Needed for normal adhesion of platelets to sites of injured endothelium

    • Serves as a carrier for Factor VIII, which also protects vWF from proteolysis

      • When vascular injury occurs, this multimeric protein uncoils which results in platelet adhesion, activation and aggregation.

• Three main types of disease:

  • Type I: A partial quantitative deficiency of both von Willebrand factor and Factor VIII. This reduction is usually mild to moderate. 

    • Most common, accounting for 70-80% of cases of vWD

  • Type II: Quantitative reduction in von Willebrand Factor, with subtypes noted as A, B, M and N.

    • Accounts for 10 to 30 percent of cases of vWD

    • Patients with Type 2B vWD may have a moderate to severe bleeding phenotype that may present with thrombocytopenia during pregnancy.

      • Though uncommon, when you go through your differential for thrombocytopenia during pregnancy, you can keep type 2B von Willebrand disease on your radar!

  • Type 3 Most severe, characterized by the virtual absence of von Willebrand factor. 

    • Least common type, accounting for only 1-5% of cases.

• VWD is usually inherited in an autosomal dominant fashion

  • Baby generally has a 50% chance of inheriting this condition — obstetric/neonatal implications.

  • Rarely vWDz is inherited as an autosomal recessive condition, namely in type 3,  and some cases of type 2. 

 How do we establish a diagnosis of von Willebrand’s disease?

• Most common bleeding symptoms: bruising, epistaxis, bleeding after injury, surgery or tooth extraction, postpartum bleeding, and menorrhagia (most commonly reported symptom).

  • In addition to mucocutaneous and soft tissue bleeding, joint and muscle bleeding can also occur.

  • Severity of bleeding is usually related to the degree of von Willebrand factor and Factor VIII deficiency. 

• Initial work up typically consists of nonspecific tests such as a CBC, PT, PTT and fibrinogen which are helpful in excluding a clotting factor deficiency.

  • PTT may be normal in patients with von Willebrand’s.

  • If thrombocytopenia is detected, type 2B vWDz is in the differential.

• Next step are tests that are specific for von Willebrand Disease, three:

  • von Willebrand factor antigen (vWF:Ag) measures the quantity of von Willebrand Factor protein in the plasma.

  • Factor VIII assay measures Factor VIII activity which is essentially a surrogate marker for the activity of von Willebrand factor.

  • von Willebrand factor activity a functional assay that measures the interaction between VWF and platelets.

    • Historically this was measured by the von Willebrand Factor ristocetin cofactor activity assay (VWF:RCo).

    • Consultation with hematology will be helpful with diagnostic testing and interpretation of results. 

Why does von Willebrand’s disease matter for us in OB/GYN?

• Strong association between von Willebrand Disease and heavy menstrual bleeding.

  • Among women with heavy menstrual bleeding, von Willebrand Dz is found to be the etiology frequently, with a reported prevalence ranging from 5 to 20%. 

• Many treatment options are available for women with von Willebrand disease and heavy menstrual bleeding, including hormonal and nonhormonal therapies.

  • Association of VWD with other gynecologic problems, including ovarian cysts, endometriosis, and leiomyomas is unclear. 

• Prior to procedures as egg retrieval if IVF is planned, or invasive procedure during pregnancy such as CVS and amniocentesis, DDAVP or VWF concentrates can be administered immediately prior to these procedures (more on treatment later).

Antepartum and Intrapartum Management of vWD

• Both von Willebrand Factor and Factor VIII levels increase during pregnancy, an increase that usually starts in the second trimester and peaks in the third trimester.

  • The increase in VWF and FVIII levels usually reduces the likelihood that our patients warrant treatment during the antepartum, intrapartum or even postpartum period.

  • If a patient was previously undiagnosed, the increase in levels during pregnancy may obscure the diagnosis.

    • In general, women with baseline levels of VWF and FVIII of >30 U/dL, suggesting type 1 VWD, usually have a high likelihood to achieve normal levels by the end of pregnancy.

  • In the case of the severe and uncommon type III vWDz, both VWF and FVIII levels do not increase during pregnancy.

• Levels of vWF and FVIII fall rapidly after delivery.

  • Levels start to approach patient’s baseline by one week postpartum and fully reach baseline by three weeks postpartum. 

• Potential complications of vwD during pregnancy include antepartum bleeding, postpartum hemorrhage and perineal hematoma which are all increased by 2–10-fold.

• Importantly the risk of delayed postpartum hemorrhage (bleeding occurring after 24 hours post-delivery) is also increased.

  • 16-29% of women with VWD will have postpartum hemorrhage within the first 24 hours of delivery,

  • 20-29% of women will experience delayed postpartum bleeding.

  • Bleeding is frequently reported to occur more than 2 to 3 weeks postpartum.

• Factor VIII and von Willebrand Factor ristocetin cofactor activity assay are checked early in pregnancy and again in the third trimester.

  • Consult hematology to decide if any additional testing is needed

• Women with type I vwDz with Factor VIII and ristocetin cofactor activity levels less than 50 IU/dL, and no history of severe bleeding, do not require special treatment at the time of delivery.

  • They can often be cared for by the general obstetrician in a community setting if the provider is comfortable and hematology available if needed. 

• If levels are less than 50 IU/dl, the patient is at risk of hemorrhagic complications including delayed postpartum hemorrhage. These patients require treatment usually close to delivery or after cord clamping.

  • The classic teaching is to administer DDAVP.

    • DDAVP causes release of VWF that has been stored in secretory granules within the endothelium, resulting in FVIII and VWF levels three to five times above basal levels within 30‐60 minutes.

    • Effective in patients with type 1 VWD with baseline VWF and FVIII levels higher than 10 IU/dL.

    • The recommended dose of DDAVP is 0.3 μg/kg IV given over 30 minutes or 300 μg given intranasally. 

      • Onset of action of DDAVP is approximately 15-30 minutes.

      • Usually given at the time of cord clamping, but because the peak effect is 1.5 to two hours after administration, it may be more beneficial if administered during the second stage of labor or immediately before cesarean delivery. 

    • Risks: water retention that can lead to hyponatremia and seizures.

      • Need fluid restriction to less than 1L in the 24 hours following DDAVP administration.  

      • However, fluid restriction after delivery can be very difficult, and is the reason why many experts do not use DDAVP as a first line treatment.

  • Alternative: plasma derived VWF concentrates.

    • Options:

      • Plasma derived VWF concentration that contains VWF alone without Factor VIII.

      • Recombinant VWF concentrate that contains only VWF without Factor VIII.

      • Plasma derived concentrate that contains both VWF and Factor VIII.

        • The decision regarding which one of these to use will depend upon levels of both VWF and Factor VIII, what is available in your hospital and input from hematology.

Regional anesthesia

• No consensus on levels that are safe for regional anesthesia, but if levels are greater than 50 IU/dL and assuming a normal platelet count, regional anesthesia is usually considered reasonable.

• Recent ASH guidelines recommend VWF activity levels should be maintained at 50 IU/dL while the epidural is in place and for at least 6 hours after removal. 

Mode of Delivery

• Fetal status unknown in most cases —> given AD inheritance and 50% risk, best to avoid procedures such as a fetal scalp electrode.

• Operative delivery is discouraged due to the potential risk of intracranial hemorrhage - cesarean delivery preferred to operative vaginal delivery. 

• The pediatrician should be made aware of the mother’s status and male circumcision should be postponed until the baby’s VWDz status can be determined.  

  • Sending cord blood at the time of delivery for a VonWill panel is recommended to determine the status of the newborn.

Postpartum Care

• High risk of both primary and delayed postpartum hemorrhage. Perineal hematomas can be seen.

• VWF and Factor VIII levels can significantly decrease postpartum, with a return to baseline within 7-21 days postpartum.

  • These levels are typically checked in the immediate postpartum period and then periodically.

  • Hematology consultation will be valuable to help work out these details.

  • NSAIDS should be avoided in the postpartum period. 

• ASH guidelines recommend the use of oral tranexamic acid in the postpartum period.

  • Administration of one mg intravenously can be administered prophylactically immediately after delivery and continued PO for 10-14 days postpartum.

Imitators of Pre-Eclampsia

Each of the conditions we’ll discuss today could be an episode all its own, so this will be way too brief to cover these topics in detail! But it’s important to keep a broad diagnostic mind open, especially if you feel the picture doesn’t totally add up. 

Reading: Sibai: Imitators of Severe Pre-Eclampsia (2007)

Previous podcasts: Hypertension and Pregnancy Trio (3/2019)

Diagnosing Pre-Eclampsia:

• Pre-eclampsia is a syndrome - a recognizable complex of symptoms and physical findings that indicate a specific condition, but for which a cause isn’t necessarily understood. 

• We need to think about the symptoms and signs of pre-eclampsia and determine how they overlap with other diseases!

  • What else might tie together: 

    • Hypertension

    • Neurologic changes

    • Pulmonary edema

    • LFT abnormalities and RUQ pain

    • Thrombocytopenia

    • Acute kidney injury

• Some potential examples:

  • Acute hepatitis or cirrhotic liver disease

  • Lupus

  • Meningitis

  • TTP / HUS

  • Drug reactions or overdoses

  • Malignant hypertension (i.e., pheochromocytoma, renal artery stenosis)

  • Heart failure or heart attack

    • You can probably think of more if you try!

• Let’s focus this broad differential on three primary significant culprits today: Acute Fatty Liver of Pregnancy (AFLP); Thrombotic Thrombocytopenic Purpura (TTP) / Hemolytic Uremic Syndrome (HUS); and a Lupus (SLE) Flare

Acute Fatty Liver of Pregnancy

• Exactly what it sounds like -- acute fatty infiltration of the liver, typically in the 3rd trimester, leading to fulminant hepatic failure.

  • Appears to be related to defects in fatty acid metabolism -- 20% of AFLP associated with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency of the fetus. 

• Incidence: 1 in 7k-20k pregnancies.

• Risk factors:

  • Fetal LCHAD deficiency: fetal homozygosity renders it incapable of processing fatty acids, and mother (typically heterozygous) has decreased function to keep up -- thus the infiltration.

  • Prior history of AFLP

  • Multiple gestation

  • Preeclampsia / HELLP syndrome (so they can even be co-existent!)

  • Male fetal sex

  • Low BMI (<20)

  • Nulliparity

• Typical presentation:

  • 3rd trimester: most common after 30 weeks

  • Often nonspecific symptoms: nausea/vomiting, abdominal pain, malaise, headache, anorexia

  • Frequently with hypertension +/- proteinuria 

    • Reported co-existent HELLP in 20-40% of cases

  • Hypoglycemia is frequent on laboratories - from impaired hepatic gluconeogenesis

    • Additionally can see signs of acute liver failure -- jaundice, ascites, encephalopathy, DIC. 

  • Renal failure upwards of 90% of cases.

• Diagnosis:

  • Typically a clinical diagnosis -- biopsy can be performed to demonstrate fatty infiltration, but rarely performed.

  • Swansea criteria:

    • Ranges pending on reading from 6-9 positive signs. 

      • Most typically need 6 (in my experience)

    • Supposed to be done in patients without HELLP syndrome/preeclampsia, limiting utility.

  • Imaging can be performed, but is also of limited utility in diagnosis

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Swansea Criteria (UpToDate)

• Treatment of AFLP:

• Supportive with critical care expertise! 

• Have ongoing monitoring for:

  • MELD score (Model for End-Stage Liver Disease) - high MELD > 30 associated with increased risk of maternal complications

  • Hypoglycemia: typically need infusion of dextrose-containing fluids

  • Coagulopathy

• Delivery!

  • Labor induction is reasonable if can be reasonable accomplished within 24 hours, and disease not rapidly progressing.

  • Cesarean delivery outright should be considered otherwise.

  • Betamethasone administration for FLM given, but shouldn’t delay delivery.

  • Magnesium as indicated for suspected preeclampsia and/or for CP prophylaxis. 

• Postpartum:

  • Mortality in AFLP is attributable to hemorrhage, liver failure, and kidney injury.

  • AFLP will often resolve within 7-10 days after delivery

  • Hemorrhagic pancreatitis is a potential and fatal complication known to be associated with AFLP - follow lipase

  • Liver transplantation may need to be considered in those with persistent fulminant hepatic failure (though this is rare). 

  • LCHAD deficiency testing should be pursued in infants.

    • LCHAD deficiency in newborns can be life-threatening!

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)

• Related but different diseases characterized by microangiopathic hemolysis, thrombocytopenia, acute renal failure, neurologic abnormalities, and fever.

• TTP - caused by deficiency in ADAMST13, a protein involved in regulating blood-clotting by cleaving von Willebrand factor from endothelial surfaces, and at the sites of vascular injury.

  • Can be familial or acquired

  • Characterized by marked thrombocytopenia - platelets frequently <20k

• HUS - can be caused by a variety of insults, but commonly Shiga-toxin from certain bacterial organisms as well as with abnormalities in complement system regulation. 

  • Renal failure is the dominating feature of HUS and tends to be particularly severe. 

• Presentation:

  • Also tends to be vague: abdominal pain, nausea/vomiting, headache, vision changes, confusion, fever

  • May also include bleeding: epistaxis, GI bleeding, petechia/purpura, hematuria (particularly in HUS)

  • Can present with or without hypertension

• Diagnosis:

  • Involve your hematology colleagues if there’s suspicion!

  • Early-onset preeclampsia may raise suspicion: 20-26ish week range, but can occur at any point

• Treatment:

  • Plasma exchange: helps to remove large multimers of von Willebrand factor and autoantibodies against ADAMST13. 

  • Steroids - help to calm autoimmune response

  • Splenectomy - helps to avoid sequestration of platelets 

  • Platelet transfusion should be avoided - may contribute to increased microvascular thrombus formation

• Delivery:

  • Not indicated immediately! PLEX and other therapies can be given opportunity to work

  • However, serial / frequent therapy is often indicated to continue pregnancy and prevent relapse

Systemic Lupus Erythematosus / Antiphospholipid Antibody Syndrome

• SLE is an autoimmune disorder with varying symptomatology but can result in significant end-organ damage

  • 30-40% of SLE patients have antiphospholipid antibodies

  • Only 1% of patients will have antiphospholipid antibody syndrome - a disorder that is characterized by microangiopathy affecting multiple organ systems, and with particularly high pregnancy risks

• Diagnosis:

  • Classically SLE diagnosis requires at least 4 / 11 American College of Rheumatology criteria;

  • However, in 2019 the ACR and European League Against Rheumatism came up with a combined criteria based on a points system:

ACR / ELAR Combined Diagnostic Criteria for SLE (2019)

• APLAS diagnostic criteria we’ve previously reviewed in our RPL episode:

• One of two clinical criteria:

  • a) Vascular thrombosis 

  • b) Pregnancy morbidity, defined as:

    • One or more unexplained deaths of morphologically normal fetus after 10 weeks of gestation by ultrasound or direct examination of fetus.

    • One or more premature births of morphologically normal neonate before 34 weeks because eclampsia or severe pre-eclampsia or recognized features of placental insufficiency.

    • Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation with maternal anatomic or hormonal abnormlaities and paternal and maternal chromosomal causes excluded.

• And one of the following laboratory criteria 

  • a) Lupus anticoagulant present in plasma on 2 or more occasions at least 12 weeks apart or 

  • b) Anticardiolipin antibody IgG or IgM isotype in serum or plasma present in medium or high titer on 2 or more occasions at least 12 weeks apart, or  

  • c) Anti-B2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >99th%ile), present on two or more occasions at least 12 weeks apart 

• Fortunately, many patients with SLE will come into pregnancy with an established diagnosis.

  • To determine if they’re having a flare to distinguish from preeclampsia, you’ll often use a serum marker for rheumatologic disease, such as:

    • Hypocomplementemia (C3 / C4 levels)

    • Anti ds-DNA antibody levels

• Symptoms are vague, as previously described with the clinical criteria for SLE diagnosis, and have overlap with preeclampsia! 

• Treatment:

  • If known from outset of pregnancy -- these patients should definitely be on aspirin for preeclampsia prevention!

  • Steroids are often used in acute flares - prednisone

  • DMARDs - safe medications for pregnancy can include azathioprine, hydroxychloroquine, and encouraging data exists for immunomodulating antibodies (i.e., adalimumab / Humira)

  • APLAS - low molecular weight heparin for prevention of VTE and pregnancy morbidity

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SIBAI 2009 (ref above)

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SIBAI 2009 (ref above)

Diabetic Ketoacidosis for the OB/GYN

What is DKA?

• Diabetic ketoacidosis is a metabolic derangement affecting primarily patients with type 1 diabetes mellitus:

  • Typically in response to some sort of stress, an insulin deficiency is encountered

    • Because of the insulin deficiency, glucose cannot be taken up and metabolized → hyperglycemia.

    • Starvation hormone pathways activate, increasing lipolysis in the liver → free fatty acids → ketosis and acidosis.

    • The liver also doesn’t have insulin to effect uptake of excess glucose, and actually begins a process of proteolysis and gluconeogenesis → worsening ketosis and hyperglycemia. 

    • The hyperglycemia will lead to glucosuria (loss of glucose via the urine), and will cause a further loss of free water and electrolytes → ultimately progressing to impaired renal function. 

• DKA may also occur in a patient with type 2 diabetes, where a severe relative insulin deficiency precipitates DKA or a related condition known as hyperosmolar hyperglycemic state (HHS). 

Diagnosis of DKA

• T1DM with a precipitating event that may cause metabolic derangement and difficulty with giving insulin therapy:

  • Infections or other acute major illness

  • A new diagnosis of T1DM

  • Non-use (accidental or purposeful) of prescribed insulin therapy

  • Use of drugs which may affect carbohydrate metabolism: steroids, terbutaline, 2nd generation atypical antipsychotic agents

  • Cocaine use

  • Malfunction of insulin pumps - less common with newer systems, but still an important contributor!

• Presentation is usually rapid onset, <24 hours:

  • Neurologic changes - confusion, stupor, coma, seizures

  • Abdominal pain - nausea, vomiting

  • Signs of volume depletion - tachycardia, dry mucous membranes, hypotension

  • “Fruity odor” due to exhaled acetone

  • “Kussmaul respirations” in severely affected patients - compensatory hyperventilation 

• Laboratory evaluation:

  • CBC

  • BMP, with anion gap calculation

    • DKA with the production of ketones will produce an anion-gap metabolic acidosis (more on that momentarily)

    • Pseudohyponatremia is often present: correct the Na value (Na concentration falls by 2 mEq/L for each 100 mg/mL increase in glucose)

    • Potassium: will often be normal on serum values, but DKA represents a state of significant relative potassium deficit due to urinary losses and shifting of potassium extracellularly with insulin deficiency

      • When insulin is replaced, potassium is driven back into cells and will lower serum potassium - so must be replaced alongside insulin therapy! 

  • UA/ketones

  • Serum ketones / beta hydroxybutyrate 

  • Urine and serum osmolality

  • ABG - especially if serum bicarbonate is very low, or hypoxia is noted

    • On a VBG or ABG - you’ll see low pH with low bicarbonate value → metabolic acidosis

      • Remember in pregnancy, bicarbonate is typically a little lower due to compensation for chronic respiratory alkalosis -- so be sure to look at that value closely! 

  • Investigation of underlying cause -- ie., cultures/imaging if infection suspected; A1c to assess control over time; amylase/lipase if pancreatitis suspected

Treatment of DKA

Important: most large institutions will have a DKA protocol! Check your institution’s policies/procedures and note that in some places, ICU admission will be required for various levels of DKA. We present some pearls here:

Two primary things to do:

• 1) Correction of fluid and electrolyte abnormalities

  • Give isotonic fluid (LR or NS) to replete extracellular volume losses and stabilize cardiovascular status.

    • If in shock, will need rapid bolusing.

    • If hypovolemic but not in shock, often start with 15-20 ml/kg lean body weight per hour for a few hours, before slowing down. 

    • If euvolemic, slower fluid infusion as clinically indicated. 

      • Most protocols will call for NS as the primary fluid -- however, the chloride load of NS may actually worsen acidosis initially! 

        • Two RCTs (only one mentioned in the podcast) have been performed in adults comparing LR to NS -- finding LR had a mild trend towards faster improvement, but there were no major differences otherwise. 

        • We bring this up as that trend towards faster improvement of acidosis in pregnancy may be of particular consideration - a faster improvement of pH may improve fetal appearance on monitoring. 

  • Fluid choice is often dictated by electrolyte concentrations:

  • Potassium should also be administered as the deficit will often be present:

    • If K < 3.3, KCl should be given at 20-40 mEq/hr, often added to the saline

    • If K 3.3 - 5.3, KCl 20-30 mEq is added to each liter of fluid ongoing

    • If K > 5.3, potassium does not need to be repleted (yet). 

      • Frequent monitoring of K is required, and may often in the initial stages need to be checked on an hourly basis.  

  • Other electrolytes can be in deficit, particularly phosphate and bicarbonate. However, these should not be directly repleted in most circumstances, with the exception of the most critically ill patients. 

• 2) Administer insulin

  • IV insulin should be given for all patients alongside potassium repletion as we already described.

    • Remember - K may look normal on the BMP, but often is in deficit!

  • Short acting insulins (aspart, lispro, or regular) are preferred at the outset; long-acting insulins should be held until patient is more stable.

    • In mod-severe disease, often start with IV bolus of regular insulin at 0.1 u/kg, followed within five minutes by an infusion of 0.1u/kg/hr. 

      • Again -- most institutions have protocols that will calculate this out for you and prevent errors in administration! 

      • The effect of these doses are to bring serum glucose down 50-70 mg/dL per hour, which is usually about as fast as it can go!

      • Once glucose is around 200 mg/dL, insulin infusion should decrease to 0.02-0.05 u/kg/hr and fluids for repletion should switch to a dextrose-containing product. 

        • If glucose falls too rapidly below 200 mg/dL, can precipitate cerebral edema/injury. 

  • Once a patient is only in mild DKA or transitioning out of it, can add longer-acting agents back.

Other considerations for pregnancy:

• Symptoms and treatment for pregnant folks are not different!

• DKA is unfortunately more common in pregnancy, as: 

  • insulin requirements increase rapidly, predisposing patients more often to potential deficiencies

  • There are more opportunities for decompensation: n/v early pregnancy, food aversions, preterm labor, use of steroids for FLM, UTI/pyelonephritis, social concern for “harming baby” with insulin.

• Recall normal pregnancy physiology is respiratory alkalosis -- so a pH of 7.36 may seem normal for most patients, but can represent significant acidosis in pregnancy!  

• Consider LR for resuscitation of the pregnant patient: potentially faster improvement of pH in the first hour of treatment due to less chloride load. 

• Consider tighter targets for glucose control with DKA (getting to 100-150 mg/dL, rather than 200, counterbalancing this with risk of cerebral edema from overcorrection). 

• During acute DKA - fetal status is often not reassuring! 

  • If mom’s pH is 6.9, baby’s is the same or worse -- manifests with absent variability, decelerations.

  • May take several hours to resolve 

  • DKA alone is not an indication for delivery!

    • It’s preferred to try to resolve the metabolic derangements before proceeding with delivery - better maternal and fetal outcomes with waiting than proceeding with delivery with unstable maternal condition. 

Female Sexual Dysfunction

What is normal sexual response? 

• Original landmark studies had a very linear model of “normal sexual response” 

  • Excitement → plateau → orgasm → resolution 

• More contemporary model is non-linear and encompasses a variety of sequences of the original four stages of as well as other stages 

  • Estrogen plays a significant role in female sexual response, including maintenance of genital tissue sensitivity, elasticity, secretions, pH, etc, as well as urinary continence, pelvic floor muscle tone, and joint mobility 

  • Approximately 43% of American women report experiencing sexual problems, with higher prevalence in women aged 45-64

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What are the different types of sexual dysfunction? 

Based on the DSM-V - 5 specific types of female sexual dysfunction:

• Female sexual interest and arousal disorder 

  • Lack of or significant decrease in at least three of the following: 

    • Interest in sexual activity 

    • Sexual or erotic thoughts or fantasies 

    • Initiation of sexual activity and responsiveness to a partner’s initiation 

    • Excitement or pleasure during all or almost all sexual activity

    • Interest or arousal in response to internal or external sexual erotic cues 

    • Genital or nongenital sensations during sexual activity in almost all or all sexuall encounters 

  • Symptoms have persisted for a minimum of 6 months and cause clinically significant distress in individuals 

• Female orgasmic disorder 

  • Marked delay in, marked infrequency of, or absence of orgasm, or markedly reduced intensity of orgamsic sensations in almost all or all occasions of sexual activity 

  • Symptoms have persisted for a minimum of 6 months and cause clinically significant distress in individuals  

• Genito-pelvic pain/penetration disorder 

  • The persistent or recurrent presence of one or more of the following symptoms:

    •  Difficulty having intercourse 

    • Marked vulvovaginal or pelvic pain during intercouruse or penetration attempts 

    • Marked fear or anxiety about vulvovaginal or pelvic pain anticipating, during, or resulting from vaginal penetration 

  • Symptoms have persisted for a minimum of 6 months and cause clinically significant distress in individuals  

• Substance/medication-induced sexual dysfunction 

  • Disturbance in sexual function that has a temporal relationship with substance/ medication initiation, dose increase, or discontinuation and causes clinically significant distress in the individual 

• Other specified or unspecified sexual dysfunction

  • Distressing symptoms characteristic of sexual dysfunction that do not meet the criteria of one of the defined categories. The major distinction between specified and unspecified is whether the clinician specifies reason that the symptoms do not meet criteria for other classes 

  • One specified reason: genitourinary syndrome due to menopause 

How should we evaluate for FSD? 

• Ask about it!

  • During routine visits, can ask questions about sexual function 

  • Ask broad, open-ended questions during routine history gathering 

  • “Many women experience concerns about sex. Are you experiencing any issues?” 

• Initial approach if patient answers yes, or if FSD is a complaint 

  • Comprehensive History 

    • Should ask detailed history about patient’s sexual and gender identity 

    • Nature, duration, and onset of symptoms - also if symptoms cause distress 

    • If patient is using medications 

    • Partner factors (ie. number of current partners, their gender, health problems, sexual function problems) 

    • Relationship quality - communication about sexual concerns with partner, past and current abuse or violence experience

    • Pain/injuries/Body image 

  • Physical Exam

    • Often, there are not specific physical exam findings 

    • However, use of mirror and pointing out female anatomy for education is sometimes helpful 

    • Can also identify if there are areas that are causing pain 

How do we treat FSD? 

• Psychological Interventions 

  • Relationship distress and partner sexual dysfunction can trigger sexual problems in other domains 

  • Options include sexual skills training, cognitive-behavioral therapy, mindfulness-based therapy, and couples therapy 

    • Sexual skills training: can include instructions in masturbation, other erotic stimulation, decrease feelings of guilt and shame with masturbation, as well as learning about anatomy (ie. clitoral stimulation)

    • Couples therapy: exercises to better communication with partner 

    • History of trauma - may need trauma-based psychotherapeutic approach  

  • Can consult or refer to mental health specialists with expertise in this area 

• Medical therapy

  • Estrogen

    • Low-dose vaginal estrogen therapy is the preferred hormonal treatment for FSD due to genitourinary syndrome of menopause  

    • Low-dose systemic estrogen can be an alternative 

    • Other alternatives include Ospemifene for management of dyspareunia due to genitourinary syndrome of menopause 

  • Androgen Therapy

    • Short-term use of transdermal testosterone can be considered for treatment of postmenopausal women with sexual interest andd arousal disorders 

    • Need to appropriately counsel that there are risks (ie. acne, increased hair growth, virilization - may be irreversible) and long-term side effects are not known 

    • Can try for 3-6 months after baseline testosterone is tested and after 3-6 weeks of initial use 

    • Should be discontinued if no effect after 6 months 

  • Flibanserin 

    • Addyi on the market 

    • Serotonin receptor agonist/antagonist and was approved in 2015 by the FDA to treat hypoactive sexual desire disorder in premenopausal women without depression 

    • However, systematic review and meta-analysis of existing studies showed that overall quality of evidence for efficacy and safety were low, and there was minimal to no improvement in hypoactive sexual desire disorder with use 

    • Black box warning against alcohol use - increased risk of syncope and hypotension 

  • Sildenafil (Viagra) 

    • Not efficacious

    • Hypothesized that it may increase pelvic blood flow to clitoris and vagina, but has not been proven to work 

  •  Bupropion 

    • If patient has antidepressant-induced female sexual dysfunction, supplementation with bupropion may improve symptoms 

•  Other 

  • For genito-pelvic pain and penetration disorders:

    • Education to help patient understand anatomy and etiology of their symptoms 

    • Vaginal dilators

    • Physical therapy (Pelvic PT) 

    • Intravaginal prasterone for treatment of postmenopausal women who have dyspareunia 

    • Lubricants and moisturizers 

      • Don’t cure the underlying cause, but may reduce or alleviate dyspareunia that is due to vaginal dryness 

        • Coconut oil is a good option, but do not use with condoms 

        • Tend to counsel more toward silicone-based lubricants because they do not dry out as quickly as water-based lubricants 

    • Vaginal lasers

      • Became a hot topic while we were senior residents and some people raved about them; latest evidence suggesting they’re not effective.

      • Vaginal CO2 fractional laser is inadequately studied for treatment of vulvovaginal atrophy 

      • Cost of treatment is rather high 

Endometriosis Part II: Treatment

How do we treat endometriosis? 

• Approach 

  • Should be based on severity of symptoms and make sure that other causes of pelvic pain are excluded 

  • Usually, medications are tried first because of the risks, recovery, and costs of surgery

  • Discussion of desire for fertility in the future can also help guide your management 

  • Review with patients that this is a chronic disease - it is not curable, but can be treated. Also, discuss that the road through treatment can be long, and that one mode of therapy that is effective for some, may not be effective for others 

• Medical 

  • NSAIDS 

    • Can be used to treat primary dysmenorrhea, and is first line for that 

    • However, no high-quality data reporting its efficacy in endometriosis; however it is low-cost and readily available; usually combined with combined hormonal therapy 

  • Estrogen-progestin contraceptives 

    • First line treatment for endometriosis because can be used long-term, well tolerated, and are relatively easy to use 

    • No formulation has demonstrated superiority

    • Both cyclic and continuous dose appear to be effective at reducing pain, but two systemic reviews reported that continuous COC regimens were more effective at reducing pain than cyclic (meaning you take the active pills in one pack → move on to the next pack, skip the placebos) 

    • This is because COCs suppress ovarian function while they are being taken and can reduce endometriosis disease activity and pain 

    • Obviously, there are risks and benefits of taking COCs, and there are many people that cannot take COCs because of the estrogen component (check out our past episode!)

  • Progestins 

    • If people can’t take estrogen, then they can use progestin only therapy 

    • Most commonly = norethindrone acetate 5 mg by mouth daily, but can be increased by 2.5 until l15 mg daily is the max

    • Depo Provera - 150 mg IM injection q12 weeks 

    • Progestins inhibit endometrial tissue growth. It also doesn’t carry the risk of VTE with COCs, and avoids risk of bone loss and menopausal symptoms associated with GnRH agonists

    • However, side effects include increased breakthrough bleeding, weight gain (Depo Provera), mood changes 

    • Alternatives: Etonogestrel implant - observational trial of 41 women showed it decreased intensity of endometriosis-related pain

    • LNG-IUD - limited evidence, but postop IUD can reduce recurrence of dysmenorrhea in women with surgically confirmed endo 

  • Gonadotropin-releasing hormone agonists 

    • I.e., leuprolide; others are things like buserelin, goserelin, etc 

    • Meta-analysis shows they are more effective than placebo, and just as effective as other medical therapies 

    • Common doses: Leuprolide 3.75 IM qmonth or 11.25 mg q3 month 

    • However, remember that it is a GnRH AGONIST 

      • Initially, can worsen symptoms for a little bit due to initial surge of LH and FSH before eventually suppressing the HPO axis (warn patients about 7-14 days of worsening symptoms) 

    • To counteract the hypoestrogenic effects (ie. menopausal symptoms, vasomotor symptoms), usually will do add-back therapy with 5 mg oral norethindrone 

  • GNRH Antagonist 

    • Also suppress HPO axis, but does so immediately, without initial LH and FSH surge like agonists 

    • Also induces a hypoestrogenic state and can cause vasomotor symptoms, as well as leads to decrease in bone density  

    • Easier to dose because they are oral rather than IM 

    • Ex: elagolix (Orilissa), dosed 150 daily up to 200 mg twice daily 

  • Danazol

    • Can be effective in reducing pain, but not common because it can cause androgenic side effects  

  • Aromatase inhibitors 

    • Usually reserved for severe, refractory endometriosis-related pain 

    • Often used in combination with progestins 

    • Off-label use of AI 

    • Limited data overall, but does seem to decrease pain compared to placebo 

    • Similarly, can cause hypoestrogenic side effects 

  • Neuropathic pain treatments 

    • Can be used if there is still pain from endometriosis (see other below)  

• Other 

  • Often, long-lasting pain from endometriosis can become chronic pain 

  • See our chronic pain episode → basically can lead to a cycle of lowered threshold of stimulus to cause pain, central sensitization 

  • May also need other therapy such as pelvic floor PT

  • May need neuropathic pain treatments (ie. gabapentin) to decrease sensitization. Remember to remind your patients that gabapentin does not take pain away immediately, and needs to be used consistently for several weeks 

• A note on opioids 

  • Patients with endometriosis and pelvic pain may receive opioids for pain relief when presenting for treatment urgently 

  • Opioids should be used sparingly or avoided for endometriosis and CPP because they only treat symptoms and do not address the issue 

  • Can lead to dependence and overuse 

• Surgical 

  • There are many, many surgeries out there for endometriosis, from simple ablation, to adhesiolysis, to nerve transections, to hysterectomies. We will cover a few 

  • Surgery offers the benefit of definitive diagnosis, but risks include damage to organs (especially if there is heavy burden of endometriosis as well as adhesions) like bladder and bowel

  • Most people will achieve initially pain relief after surgery - women who underwent operative laparoscopy were 3x more likely to report improvement in pain at 12 months than controls who had diagnostic laparoscopy (one study showed 73 vs 21%) 

  • However, nearly 20% of patient will undergo repeat surgery within 2 years because of recurrent symptoms, and risk of symptom recurrence is as high as 40% at 10 year follow up 

  • Risk factors for persistent or recurrent pain: incomplete excision, ovarian cyst drainage instead of cyst excision, and ovarian conservation

  • Endometriosis tends to get better with Menopause, and so longer latency to menopause gives more time for symptoms to recur 

  • Postoperative medical therapy: ASRM advises posteropative medical suppressive therapy for most women treated surgically 

    •  6-24 months of suppression can reduce symptom recurrence and thus potentially avoid need for multiple surgeries 

    • Best evidence comes from 2 systemic reviews: one using LNG-IUD, and another for postoperative use of COCs for prevention of relapse 

• Surgical techniques

  • Laparoscopy generally favored over laparotomy because less invasive and improves visualization, with better recovery and shorter hospital stay, elss pain 

  • Conservative 

    • Excision or ablation of endometriosis lesions with intent of preserving the uterus and as much ovarian tissue as possible 

    • First line option for most people who want surgery for endometriosis because it preserves fertility and hormone production

    • Remember: even in young patients who don’t want fertility, hormone production is necessary for bone and cardiac health!  

    • Less invasive and morbid than definitive surgery, and there is documented short term efficacy 

    • 2014 systematic review: decreased pain and increased live birth rate after conservative surgery 

    1. Disadvantages: 

       1. Rate of recurrent symptoms is higher compared to definitive surgery 

       2. Rate of reoperation increases with time, whereas it is relatively stable with definitive surgery 

  1. Hysterectomy without oophorectomy 

     1. For patients who have debilitating symptoms and whom have completed childbearing 

     2. Failed both medical therapy and at least one conservative treatment procedure 

     3. Also reasonable if other indications for a hyst (ie symptomatic fibroids, prolapse, etc) 

     4. Effective treatment for pain symptoms from endometriosis, with reoperative rates that are relatively low (19% in one study, compared to 58% in people undergoing conservative therapy) 

     5. Disadvantages 

        1. Longer, more morbid surgery with higher rates of complication 

  2. Hysterectomy with oophorectomy

     1. Those who would benefit are those with extensive adnexal disease and those for whom the risks of reoperation outweigh the risks of premature menopause 

     2. Likely increases the efficacy of definitive surgery but is accompanied by quality of life issues and potential adverse outcomes due to early menopause 

     3. Reason to do it: endometriosis is an estrogen-dependent disease, and tends to get better with menopause 

     4. Early menopause (<44 years) is associated with increase risks of overall mortality, cardiovascular disease, neurologic disease, osteoporosis