Progestins

Today we welcome Dr. Ben Brown, who is an assistant professor in the Division of Emergency Obstetrics and Gynecology at Women and Infants Hospital and the Warren Alpert Brown School of Medicine. Dr. Brown is also completed a fellowship in Family Planning, and thus shares with us his expertise in progestin-based contraception!

We quickly reviewed initially that progesterone naturally serves as an inhibitory feedback to luteinizing hormone during the menstrual cycle. There were also a number of downstream effects of progesterone, including cervical mucus thickening, stabilizing the endometrial lining, and down-regulating both systemic progesterone and estrogen receptors — you can review all of these again with our episode on the menstrual cycle if you missed it. These mechanisms of action underlie the way progestins work clinically. We do not cover the anti-progestins (mifepristone) and selective progesterone receptor modulators (ulipristal) today.

We then reviewed the generations of progestins. As Dr. Brown states, knowing drosperinone as a 4th generation is probably a good thing, but otherwise some of this is just good to know as a “contraception nerd.” The generations are summarized below in a nice table:

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Dr. Jose Antonio Guerra Guirao

We then spoke about the delivery methods beyond the drugs — pills, injections, IUDs, implants, and more!

Side effects and contraindications are important to know for all forms of contraception. Here are a few that we review:

• Androgenicity: more apparent in combined-hormonal methods, due to upregulation of SHBG by estrogen. Some progestins (particularly 1st generation) also competitively bind androgenic receptors — even sometimes if given without estrogen, those progestins may actually produce androgenic side effects! That said, this is quite uncommon.

• Thrombosis: this can be very confusing and controversial:

  • Estrogen-containing methods will raise risk of both venous and arterial clots.

    • Drosperinone and other later-generation progestins has received poor press due to higher risk of thrombosis in combined formulations. The risk is overall still very low: 7-13 events per 10,000 woman years. But compared to pregnancy as a competing outcome, 20-30 events/10k woman years, and postpartum 40-60/10k woman-years!

  • Progestins alone can also raise arterial thrombus risk.

    • These are patients who you consider to have significant endovascular risk factors — longstanding poorly-controlled diabetes, coronary disease, heavy smoking, etc. This is because progestins can shift lipid profiles to a more androgenic appearance - lower HDL, higher LDL and total cholesterol.

  • The CDC’s US MEC guidelines are an excellent tool to cross-reference comorbidities against contraceptive methods.

• Breast cancer: current or prior is a relative contraindication to hormonal contraception.

• Severe liver disease: contraindicated due to impaired hepatic processing of steroid hormone.

• Bariatric malabsorptive procedures: may not be great candidates for progestin-only pills due to need for consistent dosing time.

Urinary Incontinence

On today’s episode, we visit with Dr. Kyle Wohlrab, who is an associate professor and urogynecologist at Brown University / Women and Infants Hospital of Rhode Island. He takes us through the basics of urinary incontinence.

Urinary incontinence is quite common: almost 1/3 of women in their lifetime. The Women’s Preventive Services Initiative even recommends annual standardized incontinence screening for women annually.

The mechanisms of incontinence include:
Stress - leakage with Valsalva (sneeze/laugh/cough/activity). Generally in small volumes.
Urge - aka overactive bladder; spasms or overactivity of bladder detrusor muscle that can prompt large volume leakage.
Mixed - a combination of the above; often one of the above types is “predominant.”

We review in the podcast many of the most important parts of a history and workup, but the most important aspect are the patient’s goals with respect to incontinence. This also will guide our therapy. Childbirth, obesity, and activities involving heavy weight bearing are some common risk factors.

One of the tests that can easily be performed, but many have limited experience with, is a simple cystometrogram. Essentially, one backfills the bladder. If during filling, one sees a rise in the meniscus, this is suggestive of detrusor overactivity. After filling with 200-300cc,, one can do a filled cough stress test to evaluate for stress incontinence.

Treatments vary by type of incontinence, but can be broken down into three categories for each type:
Stress - pelvic floor PT, vaginal inserts, and surgical therapy — midurethral sling, Burch urethropexy, urethral bulking.
Urge - pelvic floor PT and behavioral modification, medial therapies, and surgical therapies — neurostimulators.

For medical therapies for urge incontinence, antimuscarinic therapy is generally first line. Oxybutynin and trospium are the most commonly used medications in this class. Recall that antimuscarinic drugs have the “slow down” side effects of dry mouth/dry eyes, constipation, abdominal pain, and sedation. Newer medications in this class can have fewer side effects but can have difficulty with insurance coverage. Trospium is the newest medication that also doesn’t cross the blood-brain barrier, limiting neurologic side effects — especially useful in the elderly!

Beta agonists are another option for medical therapy with mirabegron. Rather than acting on muscarinic receptors, these act on beta agonists. These thus should be avoided in patients with uncontrolled hypertension.

When should someone refer to urogynecology? Dr. Wohlrab’s advice is to refer once someone has failed a line of therapy, or when patients begin looking for surgical therapy. Especially after listening today, we hope you’re comfortable with this workup and treatment!

Further reading from the OBG Project:
Urinary Incontinence – How to Make the Diagnosis in Your Office and When to Refer
Treating Urinary Incontinence Without Surgery: Options and Pearls
Prolapse and Stress Incontinence: Burch Procedure vs Midurethral Sling
Surgery for Urinary Incontinence – When the Sling’s the Thing

The Menstrual Cycle

On today’s episode we welcome Dr. Jay Huber. Jay is a 3rd year fellow in reproductive endocrinology and infertility at the Warren Alpert Brown School of Medicine, and today he demystifies the HPO axis, the menstrual cycle, and all of the hormonal interplay.

It’s always helpful to follow along to one of the “menstrual cycle” diagrams, one of which we include here for reference:

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Wikipedia

As Dr. Huber reminds us, the ovary really runs the show due to its negative feedback effect on the hypothalamus. However, thinking top down:

• GnRH is release from the hypothalamus in a pulsatile fashion, triggering release of FSH and/or LH, depending on the timing of the cycle.

• In the follicular phase of the ovary, FSH stimulates development of a dominant follicle. Once the dominant follicle is large enough, it produces a high enough level of estrogen to give positive feedback to the hypothalamus. Further GnRH is released, promoting preferential LH release downstream, until an LH surge is triggered, giving us the ovulation event on day 14.

• After this, the levels of LH and FSH decline in response to negative estrogen feedback, in the luteal phase of the ovary.

• Simultaneously, the estrogen produced by the dominant follicle in the ovarian follicular phase above causes downstream effects on the endometrium, marking the proliferative phase here of endometrial growth in preparation for implantation.

• Once the follicle releases the oocyte, the follicular cells become the corpus luteum, which then produces progesterone. Progesterone matures the endometrium to be ‘pro-gestational’ for implantation and the secretory phase of endometrial maturation occurs.

• If no fertilization event occurs, the corpus luteum degenerates, and by day 23-25, progesterone withdrawal results in shedding of the endometrial lining. If a fertilization event occurs, beta-hCG prompts the corpus luteum to continue to make progesterone.

Further reading from the OBG Project:
Get updates on this and more content, as well as other awesome features for FREE if you’re a PGY-4 — sign up for OBG First!
Managing AUB-O
PCOS: Making the Diagnosis

Herpes Simplex

Today we get back on track in our STI saga with herpes simplex!

Clinically speaking, the most important thing to remember is the treatment of HSV, which is summed up nicely in the CDC guidelines. That said, we’ve tried to put together a little table for ease of reference here.

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In pregnancy, suppressive therapy should be initiated at 36 weeks with one of two regimens: acyclovir 400mg TID or valacyclovir 500mg BID.

We also don’t discuss much about disseminated HSV infection or neonatal HSV infection in today’s podcast. These can be devastating to adults and neonates alike, but we will touch on the neonatal aspect in a future episode on TORCH infections.

Find additional resources at The OBGProject!
- STD Screening in Pregnancy
- Ulcerative Genital Conditions in HIV-positive Patients

Menopause Part II: Hormone-Replacement Therapy

Today we’re talking on menopause once more with Dr. Renee Eger, assistant professor and clinician educator at the Warren Alpert Medical School of Brown University. We spend the second half of our menopause series reviewing HRT and the Women’s Health Initiative (WHI).

You can read more about the WHI here. The study really is two study methodologies in one: there were up to three randomized-controlled trial arms, and an observational arm. The components concerning HRT are dealt with through one of the RCTs.

The RCT dealing with HRT enrolled women into one of three arms: a placebo, an estrogen-only arm in patients without a uterus, or and estrogen-progesterone combination in patients with a uterus. The study was halted at 5.2 years in the E-P arm due to an increase in coronary heart disease, breast cancer, VTE, and stroke, which outweighed a benefit noted in colorectal cancer and fracture risk. The E-alone arm was stopped at 6.8 years average follow up, when the risk of heart disease was found not to be different than placebo.

Subsequent studies, including the Heart and Estrogen/progestin Replacement Study (HERS) have demonstrated at least that E-P and E should not be used for primary or secondary prevention of coronary disease, and thus HRT should not be prescribed for these indications. However, many benefits are particularly pronounced in younger patients using HRT. Thus, the position of the North American Menopause Society (NAMS) reads (emphasis ours):

“For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is most favorable for treatment of bothersome VMS and for those at elevated risk for bone loss or fracture.

”For women who initiate HT more than 10 or 20 years from menopause onset or are aged 60 years or older, the benefit-risk ratio appears less favorable because of the greater absolute risks of coronary heart disease, stroke, venous thromboembolism, and dementia.

”Longer durations of therapy should be for documented indications such as persistent VMS or bone loss, with shared decision making and periodic reevaluation. For bothersome GSM symptoms not relieved with over-the-counter therapies and without indications for use of systemic HT, low-dose vaginal estrogen therapy or other therapies are recommended.”

How should you prescribe HRT or other medications to relieve VMS? Below is a summary from ACOG PB 141. Check out CO 565 and CO 556 as well if you are really interested in the topic!

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