Pregnancy & Infant Loss Awareness Month

Treatment to Prevent Miscarriage? Review of a Case Report

By: Jolie Brustein Cotler, DO

Director’s Note: Last week, we published a review of research co-authored by family physician, NeoFertility founder, and FACTS speaker, Dr. Phil Boyle. Our series continues with this summary of a case report by Boyle et al published in Frontiers in Medicine earlier this year. [1] Former FACTS elective participant, Dr. Brustein Cotler, summarized the article, which follows a woman’s experience with recurrent pregnancy loss and the treatment that contributed to a successful pregnancy. The treatment targeted suboptimal ovulation and inadequate corpus luteum development as well as mood and menstrual disorders related to hypoandrogenemia. Learn more about Dr. Boyle and his approach to restorative reproductive medicine in our on-demand CME course and at the FACTS virtual conference on October 18-19, 2024!

Introduction

Hypoandrogenemia, or female androgen insufficiency syndrome, is characterized by reduced levels of androgens, including dehydroepiandrosterone sulfate (DHEA-S), DHEA, androstenedione, testosterone, and dihydrotestosterone (DHT). Low levels of androgens have the potential to impact ovarian follicle development, sexual function and libido, bone mineral density, and mood. [3] Adequate ovarian follicle development and ovulation are necessary to achieve a healthy corpus luteum, which forms from the remnant of the ruptured follicle. The corpus luteum produces progesterone and estradiol, which maintain the pregnancy until the hormones produced in the placenta rise at about 8-10 weeks gestation.

“Low levels of androgens have the potential to impact ovarian follicle development, sexual function and libido, bone mineral density, and mood.”

The American College of Obstetricians and Gynecologists (ACOG) defines recurrent miscarriage, or recurrent pregnancy loss, as two or more miscarriages, with less than 5% of people experiencing two miscarriages consecutively. [2] The remainder of this review will focus on a case report by Boyle et al [1] about a patient with a history of recurrent pregnancy loss, and the comprehensive approach that eventually led to delivery of a healthy baby.

Case presentation

The patient is a 30-year-old G6P1141 woman who presented with her 35-year-old husband to the Restorative Reproductive Medicine clinic with the goals of identifying the root cause of her recurrent pregnancy loss as well as achieving and maintaining pregnancy. The couple had no relevant past medical history. She was on no medications and had no family history of pregnancy loss. Below is a summary of her prior pregnancies:

• 2012: spontaneous loss at 8 weeks gestation
• 2014: full-term healthy pregnancy with a healthy baby born via cesarean section
• 2016: spontaneous loss at 8 weeks gestation
• 2017: spontaneous loss at 8 weeks gestation
• 2019: spontaneous loss at 16 weeks gestation; parental karyotyping did not yield explanation for recurrent loss
• 2019: intrauterine fetal demise at 24 weeks gestation; no anatomical or chromosomal abnormality identified in fetal postmortem examination

Clinical evaluation

The patient began tracking her cycles using the NeoFertility app with proper guidance to identify her fertile window and the day of presumed ovulation (DPO). Her cycles were a normal length of 28 to 30 days. Despite a normal menstrual period consisting of 4-5 days of bleeding, she experienced fatigue, low mood, anxiety, and dysmenorrhea. Several blood tests were done on cycle day 3, with additional testing for progesterone and estradiol levels 7 days post-DPO and ovarian ultrasounds to confirm ovulation and assess its quality.

Blood testing on cycle day 3 revealed borderline low levels of total testosterone and a low free testosterone index, as well as low DHEA-S measuring 1.8 μmol/L (ref: 2.7-9.2 μmol/L), indicating hypoandrogenemia. Blood testing done 3 days post-DPO revealed a normal estradiol level at 650 pmol/L but a progesterone level of 45.6 nmol/L (ref: 5.3-86 nmol/L). Although this progesterone level is within the ovulatory range, it is suboptimal, which may indicate poor corpus luteum function and, thus, poor quality ovulation.

Treatment

The goals of treatment were to achieve adequate ovulation and maintain estradiol and progesterone levels that were sufficient to support a pregnancy, limiting the chance of pregnancy loss. The treatment plan included naltrexone 4.5 mg nightly, DHEA 25 mg twice daily, clomiphene 50 mg daily for 5 days starting on cycle day 3, hCG 10,000 IU with LH surge mid-cycle, and hCG 2,500 IU taken 3, 5, and 7 days after ovulation during the luteal phase.

“The goals of treatment were to achieve adequate ovulation and maintain estradiol and progesterone levels that were sufficient to support a pregnancy, limiting the chance of pregnancy loss.”

Pregnancy was achieved after two cycles of targeted intercourse while charting with NeoFertility. Serum estradiol, progesterone, and hCG levels were monitored weekly for the first 3 weeks, and serum estradiol and progesterone levels were monitored every 4 weeks for the remainder of the pregnancy. Treatment to help maintain the pregnancy included DHEA 20 mg daily, Cyclogest® (progesterone) 400 mg pessaries vaginally twice daily, and naltrexone 4.5 mg nightly. On this treatment, the patient’s hormone levels remained stable and supported the pregnancy. At 36 weeks gestation, she delivered a healthy baby via elective cesarean section.

Discussion

The etiology of recurrent pregnancy loss is multifactorial and an explanation is often elusive. In this patient, the presumptive root cause was suboptimal ovulation yielding a suboptimal corpus luteum; thus, a treatment plan was selected to target those areas. Other therapies targeted hypoandrogenemia evident by the low DHEA-S level, as well as the patient’s low mood and dysmenorrhea.

Based on the low progesterone levels 7 days post-DPO, the corpus luteum was not making enough progesterone to maintain a pregnancy. DHEA, which is eventually converted to estradiol, was given to support the maturing follicle. Clomiphene was given to stimulate follicle development, and hCG was given at the time of the LH surge to ensure adequate rupture of the follicle. Once the follicle ruptures, the next step is to ensure adequate progesterone levels, which should be above 60 nmol/L at 7 days post-DPO. To help the corpus luteum increase production of progesterone, hCG is given at 3, 5, and 7 days post-DPO.

Naltrexone was given to treat dysmenorrhea, fatigue, anxiety, and low mood caused by hypoandrogenemia; DHEA is also used to treat the hypoandrogenemia. As the ovaries take time to normalize in patients with hypoandrogenemia, DHEA should be started 8-10 weeks prior to attempting conception. After pregnancy was achieved in this patient, naltrexone was continued to provide mood support, progesterone was given to continue to support the pregnancy, and DHEA was given to continue to treat the hypoandrogenemia.

“Naltrexone was given to treat dysmenorrhea, fatigue, anxiety, and low mood caused by hypoandrogenemia; DHEA is also used to treat the hypoandrogenemia.”

Conclusion

Hypoandrogenemia, diagnosed both clinically and based on laboratory findings, may be one of the many factors that influence fertility. Treating a patient with recurrent pregnancy loss requires a multifaceted approach. Identifying and treating hypoandrogenemia in these patients has been a successful strategy as part of the treatment plan to achieve and maintain a healthy pregnancy.

References

[1] Boyle PC, Pandalache C, Turczynski C. Successful pregnancy using oral DHEA treatment for hypoandrogenemia in a 30-year-old female with 5 recurrent miscarriages, including fetal demise at 24 weeks: a case report. Frontiers in Medicine. 2024;11. doi:10.3389/fmed.2024.1358563
[2] Repeated Miscarriages. ACOG. Updated January 2023. Accessed March 7, 2024. https://www.acog.org/womens-health/faqs/repeated-miscarriages
[3] Udoff LC. Overview of androgen deficiency and therapy in females. UpToDate. Updated Nov 30, 2023. Accessed March 6, 2024. https://www.uptodate.com/contents/overview-of-androgen-deficiency-and-therapy-in-females?search=female%20androgen%20insufficiency%20syndrome&source=search_result&selectedTitle=1%7E150&usage_type=default&display_rank=1

ABOUT THE AUTHOR

Jolie Brustein Cotler, DO

Jolie Brustein Cotler, DO is a recent graduate of Touro College of Osteopathic Medicine in Middletown, NY. She also earned a Master of Science in Interdisciplinary Studies in Biological and Physical Sciences at Touro College of Osteopathic Medicine, and a Bachelor of Arts in Biology from State University of New York at Oswego. Dr. Brustein Cotler plans to pursue medical residency in obstetrics and gynecology and hopes to serve as an advocate for her patients. She enrolled in the FACTS elective to expand her knowledge of family planning and hopes to use the tools from this course to educate and equip future patients to make informed choices about their bodies.