Practical Reproductive Medicine for the Primary Care Provider (Uzelac, 5/12/2021)

Many thanks to Dr. Peter Uzelac, medical director of the Marin Fertility Center, who gave a really great presentation this week on reproductive medicine  for primary care providers. He covered a lot of important topics that are not bread and butter for us, but that are definitely important to understand and consider in caring for patients of reproductive age. Dr. Uzelac also gave us some great insight as to what patients can/are doing themselves and what we can/might recommend.

For those of you who want to see the presentation, a video recording is available HERE.

For my notes, keep reading. . . 

Optimizing Natural Conception: 

• the "fertile window" is a 6 day interval when conception is possible, ending on the day of ovulation
• frequency of intercourse recommended for optimal fertility success: q1-2 days in the fertile window (though 2-3 times/week nearly equivalent)
• there is no substantial evidence that monitoring increases success
• it turns out that changes in cervical mucus performs as well or better than basal body temperature (BBT) or urinary LH
• no timing, position, resting around sexual intercourse have any impact on fertility
• moderate alcohol (1/day) or moderate caffeine (1 cup coffee/day) is probably okay
• smoking, recreational drugs (including marijuana) are not good

Causes of infertility: 

• male factor 30% 
• diminished ovarian reserve 30%
• ovulatory dysfunction 10%
• tubal/peritoneal 20%
• unexplained 10%

When should someone be evaluated for infertility?

In the absence of a remarkable history or physical findings, treatment should be started if no pregnancy results after active attempt for pregnancy within:

• 12 months for women <35 (85% of couples trying to get pregnant will be successful after 12 months)
• 6 months for women >35
• Immediate evaluation and tx for women >40

3 "Tiers" of Diagnosis and Treatment of Infertility

• Tier 1: for all couples; focus on the basics: eggs, uterus/tubs, sperm
• Tier 2: ~15% of people; more focused, newer diagnostics, less validates (endometriosis, chronic endometritis, molecular sperm assessment, things only seen during ovarian stimulation or embryo culture)
• Tier 3: difficult/rare cases, after multiple treatment failures (immunomodulation, uterine microbiome) 

What historical clues can help?  

• Menstrual history:
• Intervals: 28 days +/- 7 is considered normal
• abnormal uterine bleeding (structural, hormonal, endometriosis)
• pain/dysmenorrhea (endometriosis)
• Duration of infertility: unsurprisingly, the longer the problem, the harder to solve
• Gs and Ps
• How many children desired? (start planning with first child--> embryo banking)

What physical clues can help?

• ultrasound (cysts, polyps, fibroids, adenomyosis)
• BMI (extremes, upper and lower)
• androgen excess (especially in oligomenorrhea)
• Thyroid

How do you know a woman is ovulating? There are many ways to detect, none are perfect

• Of note, 1-12% of normal women's cycles are anovulatory (more likely in extremes of reproductive age)
• You can detect ovulation through a variety of methods:
• mid cycle symptoms: discharge, mittelschmerz
• moliminal symptoms (fluid, breast tenderness, craving, mood)
• hormones: LH surge, mid-luteal progesterone (normal is >3ng/ml, drawn one week prior to expected menses rather than on a specific cycle day; levels may vary 7-fold even within hours)
• Ultrasound: dominant follicle, corpus luteum cysts

What patients may be doing to detect ovulation? Tracking w/apps, diary good start but women get too focused on these, urine ovulation kits (detect both LH surge and estrogen surge as well), wearables, post-ovulatory progesterone kit. All can be used to demonstrate ovulation and time intercourse. 

Pearl: Eumenorrheic patients with sporadic anovulation doesn't impact fertility. They will eventually get pregnant over the 12 month interval! Many women get very focused on this step. Try to have patient focus less on ovulation if they are generally ovulating.

What about ovarian reserve? This is often the most important factor in fertility; age is so impactful on chances for successful pregnancy. Plus, fertility doctors can fix almost anything EXCEPT ovarian reserve

• all eggs a woman will ever have are present at birth
• apoptosis occurs through a woman's lifetime
• egg survival falls more around age 35/37, fertility ends early 40s, but menopause doesn't happen until closer to 50
• for a woman's last 10 years, she often has  regular periods but not able to get pregnant
• last child statistically  is age 42, pregnancy is possible but not probable after 43

Ovarian reserve testing: REI no longer use FSH/E2 (not sensitive enough), or provocative tests, really test of choice is anti Mullerian hormone (AMH)

• AMH is more sensitive than FSH (can be done on OCPs, needs to be adjusted by 30%). 
• A follow-up test: antral follicle count (on ultrasound)

Of note, these markers are poor predictors of fecundability , they mostlyt help to characterize where a patient is on their fertility timeline, not really a great test to predict pregnancy. REI uses them to predict response to stimulation in IVF

What patients are doing? At home "hormone testing" not well validated, often include hormones not assessed at the same time as other hormones, so not great. Would NOT recommend.

Fertility ultrasound (Antral follicle):

What you are looking for on ultrasound:

• early resting follicles 2-10mm
• dominant follicle 20-28mm prior to ovulation
• corpus luteum cyst left behind right after ovulation

Uterus/tubes:

• For tubes: hysterosalpingogram (HSG): proximal and distal tube occlusion, adhesions, etc
• not great for uterine cavity visualization, cannot differentiate septate from bicornuate uterus
• bilateral FILL and SPILL, delays in fill/spill, obstruction (proximal vs. distal), hydrosalpinx
• For uterus: saline sonogram (hysterosonography) defines size and shape of uterine cavity (91% sensitivity, 84% spec for intrauterine pathology: polyps, myomas, synechiae)
• hysteroscopy is not typically done unless plan for intervention (e.g. ablate septum, polypectomy)

Male factor:

• history: prior fertility, erectile or ejaculatory dysfunction, anabolic steroid use (testosterone, previous abdominal or scrotal surgery, STD
• semen analysis: concentration, motility, morphology
• see WHO guidelines below for normal values
• results are a SPECTRUM: more abnormal parameters, the higher increase in fertility problems
• only a spot check, lots of fluctuations (should be repeated if abnormal)

What are patients doing? Home semen analysis is available: 

• Yo test ($50)
• Fellow: send in kit, conventional semen analysis  ($170)

Tier 2 conditions to consider:

• Endometriosis, underdiagnosed, classically a surgical diagnosis, now fertility doctors using specialty markers
• Chronic endometritis
• Microbiome

Reproductive Therapeutics 

"Simple fixes"

•  Polypectomy, ovulation induction in PCOS, IUI for mild male factor, etc

Superovulation and Intrauterine insemination (IUI) for women <37

• Clomid or letrozole x 5 days
• IUI (with sperm washing)

*NEW guidelines 2020: Immediate IVF should be offered in women >38 years of age