This is the first study testing low-dose dexamethasone + letrozole in letrozole-resistant PCOS patients undergoing ovulation induction (OI).

Study Background

WHAT

• Assessing the efficacy of low-dose dexamethasone with letrozole (“Dexlet”) in PCOS patients who failed initial five-day treatment of letrozole for OI, regardless of dehydroepiandrosterone sulfate (DHEA-S) levels

WHY

• Patients who fail letrozole may be encouraged to move onto more invasive and expensive next steps

• Studies show adding dexamethasone to clomiphene improves ovulation and pregnancy rates in clomiphene-resistant patients

• Studies show a mixed picture of DHEA-S levels impacting letrozole resistance and ovulation rates

WHERE

• Division of Reproductive Endocrinology and Infertility, Mayo Clinic, Rochester, Minnesota

WHEN

• Retrospective chart review of September 2019 - December 2022

WHO

Inclusion Criteria:

• PCOS per Rotterdam criteria

• Ages 18-35

• Failed to ovulate after taking maximum dose (7.5mg) of letrozole for OI—> thereafter took Dexlet

Exclusion Criteria:

• Diagnosis of hyperprolactinemia, thyroid disorder, or a known infertility factor other than oligo- or anovulation

  *donor sperm were not used (coincidence vs. exclusion criteria)

HOW

• Baseline Workup

  • Hormonal assessment was completed on cycle days 3–5 if oligo-ovulatory (or random if amenorrheic)

  • Pretreatment glycemic status was assessed by either oral glucose tolerance test, fasting plasma glucose, or A1c

  • Total motile sperm count (TMSC) assessed partner sperm quality

• Fertility Treatment

  • Letrozole with started on cycle day 3 for five days; dose-escalated to 7.5 mg if insufficient ovarian follicle response

  • Woman considered letrozole-resistant if no dominant follicle (at least 14 mm) ID’d on transvaginal ultrasound after letrozole 7.5 mg —> next started seven days of dexamethasone 0.5 mg + five more days of letrozole (Dexlet)

  • If dominant follicle seen on repeat ultrasound, women used ovulation predictor kits (OPKs) or took human chorionic gonadotropin (hCG) 250 mcg with timed intercourse or intrauterine insemination (IUI)

  • Clinical pregnancy = gestational sac(s) seen on ultrasound

  • Live birth = delivery > 22 weeks

Statistics (Briefly)

• Wilcoxon’s rank sum, chi-square, Fisher’s exact test, and an unspecified t-test

Results

• 42 OI cycles for 28 patients taking Dexlet

• Demographics:

  • 86% Caucasian, median age 30 years, and median body mass index was 30 kg/m2

  • oligo-ovulatory cycles 57%, anovulatory 43%

  • baseline similar except nonresponders had longer duration of infertility (3y vs. 1y, P = 0.02) and DHEA-S non-significantly higher in responders

  • male partners: 22/28 had normal TMSC, 5/28 with missing data had “proven fertility,” 1/28 declined test

• Dexlet responders: 79% yes, 21% no

  • 83% of responders used hCG, 17% used OPK

  • Timed intercourse 77%, IUI 23%

• Ovulation response in 83% of cycles

• Implantation confirmed via serum (+) hCG in 41% in 1+ cycles

• Live birth resulted from 20% of Dexlet cycles and cumulatively 32% from patients in trial

  Authors’ Thoughts

• Adjuvant dex appears to effective for letrozole patients at risk of cycle cancellation

• Live birth rates similar to non-resistant PCOS patients doing OI

• Improved ovulation possibly explained by extended duration of letrozole (10 days vs. 5 days) vs. addition of low-dose dex

• Responses seen in patients with normal and high DHEA-S levels, but study not powered to evaluate DHEA-S response to dex

• Recognize lack of dex-related assessment of glucose peri and post-treatment

  This Pharmacist’s (Additional) Thoughts

(+) studied most relevant outcomes (pregnancy, live birth)

(-) Assessment of patient medication adherence not stated - did adherence impact responder rates?

(-) Unusual that zero patients reported side effects from letrozole - how were patients counseled?

Conclusions

Adding low-dose dexamethasone for seven days is likely safe and may be effective in patients initially non-ovulatory in response to five days of letrozole 7.5 mg. Since this was a small, retrospective study, prospective comparative trials could further clarify the potential benefit of Dexlet as a potential therapy for initially letrozole-resistant PCOS patients with OI.

Resources

Barbieri RL and Ehrmann DA. Diagnosis of polycystic ovary syndrome in adults. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2034. www.uptodate.com. Accessed May 20, 2023.

Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome [published correction appears in N Engl J Med. 2014 Oct 9;317(15):1465]. N Engl J Med. 2014;371(2):119-129. doi:10.1056/NEJMoa1313517

Neblett MF 2nd, Baumgarten SC, Babayev SN, Shenoy CC. Ovulation induction with letrozole and dexamethasone in infertile patients with letrozole-resistant polycystic ovary syndrome [published online ahead of print, 2023 May 2]. J Assist Reprod Genet. 2023;10.1007/s10815-023-02817-9. doi:10.1007/s10815-023-02817-9

Zhu X, Fu Y. Extending letrozole treatment duration is effective in inducing ovulation in women with polycystic ovary syndrome and letrozole resistance. Fertil Steril. 2023;119(1):107-113. doi:10.1016/j.fertnstert.2022.09.018