Today we welcome one of our colleagues, Dr. Deanna Glassman, current PGY-4 at Women and Infants / Brown University, but heading off to Houston, TX this summer to become a new fellow in gynecologic oncology at MD Anderson Cancer Center!
She shares with us her own story of applying into GynOnc and the essential facts of this field.
Today we are thrilled to have Dr. Emily Seidler of the Division of Reproductive Endocrinology and Infertility at Beth Israel Deaconess and Boston IVF, come help us revisit Infertility with a discussion on treatment. We start out with definitions of fecundity versus fecundability, meaning:
Fecundity: Fertility; the ability to conceive and produce offspring, vs.
Fecundability = probability of getting pregnant in a single menstrual cycle.
For the first six months of attempted conception, 80% of couples will succeed. After one year, this jumps to about 85%, leaving a 15% rate of infertility overall based on the definitions we reviewed in our prior infertility episode.
Patients/couples should be initially counseled on lifestyle modification to improve fertility:
Stop smoking.
Reducing excessive alcohol/caffeine consumption.
Weight loss to target normal BMI.
Appropriately timing intercourse just before/around time of ovulation.
Use of OPKs starting around CD10
Once health and lifestyle is (reasonably) optimized, treatment may still be needed and varies depending on cause of subfertility/infertility.
We then started to talk about the specific causes of infertility. The first and most broad is ovulatory dysfunction. Ovulatory dysfunction is broken into major categories by the World Health Organization (WHO):
WHO class 1: hypogonadotropic hypogonadal anovulation (5-10%)
Common causes of this include anorexia, over-exercising, or Kallman’s and Sheehan’s syndromes.
These women need extensive nutritional support and hormonal support for bone and heart health.
To conceive, this group of patients will need injectable gonadotropins.
WHO class 2 = Normogonadatropic normoestrogenic (70-85%)
The most common example in this group is PCOS.
Treatment should focus on optimizing health (weight loss, improve/control insulin resistance, etc.) then ovulation induction with timed intercourse.
Letrozole is first line ovulation induction agent with PCOS.
NEJM 2014 comparing Clomiphene and Letrozole for PCOS.
Showed LTZ was associated with higher ovulation rates and higher live brith rates.
Clomiphene can also be used if can’t use letrozole or patient doesn’t respond to letrozole.
Clomiphene & Letrozole have different mechanisms of action but similar end result:
Clomid works at the level the brain as a SERM to inhibit negative feedback of estrogen on GnRH and FSH production/release.
Letrozole works at the level of the ovary and is an aromatase inhibitor, thus reducing the amount of estrogen available and pushing more production of FSH.
Both trick the brain into thinking estrogen is low, so FSH goes up.
WHO class 3 = hypergonadotropic hypoestrogenic anovulation (10-25%)
Classically described as primary ovarian insufficiency (POI)
Some can go through treatment with their own eggs, but often FSH is very elevated and AMH/AFC are very low- these patients generally need IVF donor eggs to conceive.
Next, we moved beyond ovulation to other causes of infertility.
Tubal factor:
I.e., both tubes are blocked.
Treatment is IVF, as this is only way to bypass the tubes in this case.
If hydrosalpinx, consider removing prior to treatment (these reduce pregnancy rate by 50% after embryo transfer when left in situ).
Male factor:
If sperm is present but in low counts (generally under ~4 mil total motile sperm), IVF with ICSI is helpful
ICSI = intracytoplasmic sperm injection.
One sperm injected into each egg under the microscope
If azospermic but male factor is an obstructive cause (i.e., cystic fibrosis patients with congenital absence of vas deferens), can surgically obtain sperm with TESE (testicular sperm extraction).
If azospermic and non-obstructive (i.e., patient isn’t making sperm), need donor sperm for conception.
Uterine factor:
This is generally not an independent cause of infertility or reason, in isolation, for surgical intervention.
However, when uterine factors that affect the cavity are found in an infertility evaluation, these are typically corrected prior to treatment.
Submucosal fibroids and endometrial polyps can be removed hysteroscopically .
Uterine septum or intracavitary adhesions can be resected hysteroscopically with cold scissors or with energy.
Unexplained infertility:
Testing all normal but unable to conceive after 6-12 mos; includes age-related subfertility.
Treatment is empiric (“cover the bases” approach).
Can start with medicated IUI with Clomiphene or Letrozole
If unable to conceive after 3-4 cycles, move on to IVF.
IVF can involve a fresh embryo transfer on day 3 or day 5, or frozen embryo transfers (always day 5).
Prenatal genetic testing for aneuploidy (PGT-A) is an adjunct to treatment (formerly called PGS).
This involves a trophectoderm biopsy at the blastocyst stage
Trophectoderm becomes the placenta; inner cell mass becomes the fetus.
Embryos generally are then frozen and biopsy samples are tested to determine chromosomal status
Used as a selection tool to transfer a single euploid embryo
Theoretically increases pregnancy rate to 60-70% and decreases miscarriage rate to 10%
However, recent studies (i.e., STAR trial) haven’t shown huge benefit to PGT-A over standard morphologic criteria for embryo evaluation.
Same sex couples/single patients:
Same sex female couples have options various therapies vs. traditional IVF
TDI = therapeutic donor insemination.
simply timing insemination with one partner’s menstrual cycle and using donor sperm.
Can also utilize ovulation induction techniques (i.e., letrozole/clomiphene).
Partner-assisted Reproduction (PAR), aka reciprocal IVF = using one partner’s eggs for conception, but the other partner carries the pregnancy.
Ovarian stimulation and egg retrieval on one partner.
Create embryos with donor sperm.
Transfer the embryo(s) into the other partner’s uterus.
Traditional IVF particularly if one partner is unable to conceive using TDI.
Same sex male couples require donor egg + gestational carrier.
Gestational carrier: just carrying the pregnancy.
Donor egg from a different woman; embryos created with one of the male partner’s sperm,
Traditional surrogacy typically refers to using the carrying woman’s egg, as well as her uterus. This has become very complicated legally and ethically and thus is not used with frequency.
Today we welcome Dr. Eva Reina, who is a current PGY-3 at Brown/Women and Infants. Eva shares with us some information on one of the most clinically challenging topics in office gynecology: chronic pelvic pain.
In terms of the initial evaluation, using the PPUBS framework can be useful:
Pain: typical “can you describe your pain?”
Periods: a thorough menstrual history, which should always be part of your GYN history taking.
Urinary symptoms: timeline of symptoms with respect to urination, as well as triggers for any symptoms related to urination.
Bowels: constipation and diarrhea, depending on pattern, can relay problems such as IBS, IBD, or other functional GI disorders.
Sexual function: describing not only the nature of dyspareunia, but the timing and length of pain symptoms.
After history taking, a physical examination is the next important step. Particularly with the pelvic exam, starting with a single digit may be revelatory. Deep infiltrating endometriosis may be suggested by particular point tenderness. Bimanual examination can help to assess uterine size or concerns for adenomyosis. Speculum exam may not reveal much in the way of pain, but allows for testing for infectious etiologies.
We then discuss some of the mechanisms of chronic pelvic pain development:
Central Sensitization: Most patients with chronic pelvic pain do have multiple pain generators and may even be centrally sensitized: that is, amping up of a stimulus leading to a state of constant reactivity. This lowers the threshold of a stimulus to cause pain and also may maintain pain even after the initial insult has been removed. For instance, in population-based studies vulvodynia, IC, endo, IBS, migraines are commonly found together.
Cross-Talk:
The top-down phenomenon. The patient who has low back pain, migraines, fibromyalgia, and has now been referred to your office with chronic pelvic pain.
The bottom-up phenomenon. 30 year old female who has “always had painful periods.” Stopped OCPs 5 years ago in order to achieve pregnancy. Presenting to your office for urinary symptoms (pain with bladder filling, urgency, frequency).
Pelvic Organ Cross-Sensitization: Convergence of sensory input from the pelvic viscera, their associated striated sphincters, muscular components of the pelvic floor, lower abdominal wall, the muscular perineum and its corresponding cutaneous components.
Afferent information from the major pelvic organs (e.g. bladder, bowels, and uterus) is conducted through the hypogastric, splanchnic, pelvic, and pudendal nerves to cell bodies in thoracolumbar and lumbosacral dorsal root ganglia. At first, these signals go up to the brain (central nervous system), and an efferent signal comes back down (e.g. reflexically removing your hand from a hot stove).
Over time, if one doesn’t remove the noxious stimulus, the body thinks there must be nobody home to hear the fire alarm, let’s try the neighbor’s house. So, long-term, noxious afferent stimulation from an irritated pelvic organ (peripheral to central) leads to that sensory input traveling back down to the peripheral nervous system to pass the message along to a nearby pelvic organ that was not previously affected. This neurogenic “inflammation” via the central to peripheral pathway may even produce functional changes in the uninsulted organ with little evidence of an organic etiology (e.g. IBS, IC/PBS, vulvodynia).
Where do the muscles come in?
It is helpful to think of muscular spasm as a reactive phenomenon. If you uncover pelvic or abdominal wall myalgia, be sure to treat other primary pain generators BEFORE pelvic floor PT. If you don’t remove the stimulus, the patient is unlikely to make sustained forward progress in PT.
Pelvic floor PT is hard to come by (shortage of well-trained providers) and it is uncomfortable both physically and mentally for patients. Thus it is difficult to motivate patients to return to pelvic floor PT after a previous failure of therapy.
In today’s podcast, we try to provide an update on sepsis for OB/GYN’s. It’s a long one but hopefully full of lots of good information for your practice and knowledge.
Sepsis definitions have changed recently, put forth in 2016 the Third International Consensus Conference for the Definitions of Sepsis and Septic Shock Task Force. These marked a major departure from previous iterations, which were defined by the “SIRS” or “Systemic Inflammatory Response Syndrome” criteria. This also ushered in a new scoring system for sepsis evaluation, known as the Sequential Organ Failure Assessment tool, and a quick bedside version known as qSOFA.
Common obstetric and gynecologic etiologies include urinary tract infections and pyelonephritis; chorioamnionitis/endometritis; wound infections and necrotizing fasciitis; septic abortions; toxic shock syndrome; and ruptured tuboovarian abscess. Non-obstetric or non-gynecologic causes should also be considered. Some of these more common etiologies include gastrointestinal causes, such as appendicitis, diverticulitis, or peritonitis; respiratory causes, such as influenza or pneumonia; and skin infections including cellulitis.
In our hospital, we remember the primary interventions for sepsis using the acronym “BLAST”: Blood Cultures, Labs/Lactate, Antibiotics, Saline, Time.
B: Blood Cultures; L: Lactate/Laboratories
With the suspicion for sepsis, laboratory evaluation is essential. CBC, BMP, lactic acid, and blood cultures are often part of the initial workup.
Lactic acid production partially results from the shift of aerobic to anaerobic cellular metabolism, so it functions as a proxy marker of poor tissue perfusion. In sepsis, higher lactic acid levels have been associated with worsened outcomes. Surviving Sepsis Campaign guidelines do recommend guiding resuscitation to lactate normalization. The SMFM consensus statement does recommend lactate measurement for suspected sepsis in pregnancy.
Blood cultures are important to obtain upfront, prior to the initiation of antibiotic therapy. Even with an initial antibiotic exposure, blood cultures can become useless. Two sets of peripheral blood cultures, with each set consisting of aerobic and anaerobic cultures, are recommended (13). If an infection site is suspected and can be easily accessed for culture in a timely manner, cultures are recommended prior to antibiotic initiation.
In obstetric patients, the most common causes of sepsis include septic abortion, chorioamnionitis and postpartum endometritis, urinary tract infections, pneumonia, and gastrointestial origins such as appendicitis.
A: Antibiotics
Empiric antimicrobial therapy should be broad in coverage, but also directed towards the most likely source, if one is known. The SMFM consensus statement, the Surviving Sepsis Campaign, and the SEP-1 core measure promote administration of appropriate antibiotic therapy within three hours of presentation. Mortality risk in septic shock appears time-dependent with respect to antibiotic therapy based on observational data.
Combination or “double coverage” therapy for critically ill or neutropenic patients (using two antibiotics to cover the same spectrum of pathogen) is not recommended. However, one notable exception is a source of sepsis more commonly encountered by gynecologists: toxic shock syndrome (TSS).
TSS results from the production of noxious exotoxins by Streptococcus and is described with retained objects, such as tampons, in the vagina. The antibiotic therapy of choice in this case is a combination of penicillin and clindamycin, as clindamycin acts as a transcription inhibitor to the production of bacterial exotoxins.
S: Saline
Crystalloid fluid is the choice for initial resuscitation in severe sepsis or septic shock. The landmark trial on early-goal directed therapy (EGDT), published by Rivers in 2001, randomized patients to standard therapy versus targeted fluid therapy with placement of both central venous and arterial lines, with strict goals for mean arterial pressure (MAP), central venous pressure (CVP,) venous oxygen saturation, hematocrit, and urine output. Fluid administered prior to randomization in both arms was 20-30 cc/kg over 30 minutes. This has ultimately become the standard of care for initial fluid resuscitation.
In pregnancy, this may be overly aggressive, and predispose patients to pulmonary edema; thus, the SMFM consensus statement on sepsis in pregnancy recommends an initial bolus of 1-2 L. Frequent reevaluation of volume status should be performed.
T: Time
The SEP-1 core measure from CMS is predicated on two major time points, with time starting at the time of patient presentation with severe sepsis or septic shock. The SEP-1 bundle requirements at three hours and six hours are shown in Figure 2. The entirety of the “BLAST” protocol covers the initial, “three hour” time point.
The next marker is six hours, which states there should be a redrawn lactate if there was a diagnosis of severe sepsis or septic shock. There also should be a full physical examination, The reexamination can include central venous pressure measurement, central venous oxygen measurement, a bedside cardiovascular ultrasound, or a passive leg raise test as well. For obstetricians and gynecologists, likely the physical examination and passive leg raise are the most easily performed. This may not work in pregnancy due to aortocaval compression; thus, SMFM recommends continued bolus with small fluid volumes (250 - 500 cc) and close monitoring of vital signs to determine if patients are fluid responsive.
If patients in septic shock do not respond to fluid and are persistently hypotensive despite adequate fluid resuscitation, the SEP-1 core measure requires administration of vasopressors by the six hour mark. Norepinephrine is the primary choice in sepsis both in and out of pregnancy. Norepinephrine is associated with lower rates of arrhythmia and overall mortality compared with other vasopressors.
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We go into a lot more detail in the podcast on some additional points, but be sure to check out the SMFM Sepsis guideline for all the deep reading on this topic!
Today we welcome back Dr. Edmonson for part II of our breast cancer chat. Check out last week’s post for screening and imaging information.
From a radiographically-guided core breast biopsy, there’s a lot of things that can come back. Today we’ll focus on the pathologic concerns. Dr. Edmonson breaks this down into:
Atypical Ductal Hyperplasias / Atypical Lobular Hyperplasias / Lobular Carcinoma in Situ
These lesions predict a risk for breast cancer in the future, but are not actually cancer. These are all managed surgically, with an approximately 15% upstaging rate on final pathology after excision, most pronounced with ADH. The risk models we discussed last episode can then give an updated risk of breast cancer which may alter screening strategy (i.e., if risk exceeds 20%, MRI may be used as an adjunct). Additionally, using risk-reducing medications such as tamoxifen or raloxifene may also become appropriate.
Ductal Carcinoma in Situ (DCIS)
These are non-invasive cancers which require lumpectomy or potentially mastectomy. Thereafter, radiation is usually recommended as well as risk-reducing medications such as tamoxifen or aromatase inhibitors such as anastrozole. There is a 20-30% upstaging risk at time of surgery, and additionally additional surgery may be required to get negative surgical margins as there is no reliable intraoperative technique to detect margins.
Invasive Cancers (Invasive Ductal Carcinoma or Invasive Lobular Carcinoma)
With invasive cancer, different strategies exist. Surgery versus neoadjuvant chemotherapy or endocrine therapy may be considered based on extent of disease to reduce morbidity of surgery (i.e., more limited lymph node dissection which would reduce risk of lymphedema from axillary dissection). New surgical techniques exist now as well including lymphatic reanastamosis that is helping to improve morbidity after these surgeries.
Invasive lobular carcinoma can be difficult to identify. These are less aggressive, but they often don’t show up well on imaging and are difficult pre-operatively to get good margins.
After A Diagnosis
OB/GYNs can help to reassure patients and connect them to breast surgeons. Fewer breast cancers are requiring chemotherapy, which is often a patient’s greatest fear. Surgical techniques are improving and reconstruction is widely available, including skin-sparing and nipple-sparing techniques.
Screening will be guided by the breast surgeon. This depends more and more on the individual, the pathology and tumor characteristics, and risk for local recurrence. Recall that patients on tamoxifen are at higher risk of VTE and at higher risk of endometrial hyperplasia.
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The views expressed herein represent those of the podcast authors personally, not of their institutions.
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