What is DHEA?

Dehydroepiandrosterone (DHEA) is a steroid hormone precursor, or prohormone, that is naturally produced in the body. It is produced primarily by the adrenal glands (in the outer portion known as the adrenal cortex), which sit just above the kidneys. DHEA production and release is regulated by a hormone called adrenocorticotropic hormone (ACTH). ACTH is released from the anterior pituitary gland in the brain; it then travels through the bloodstream and “tells” the adrenal gland to release DHEA. Like other steroid-based hormones, DHEA is derived from cholesterol. After DHEA is produced, it circulates in the bloodstream and moves to other tissues in the body. DHEA is also synthesized in the brain, in theca cells which surround ovarian follicles in women,^{i, ii} and in Leydig cells within the testes in men.ⁱⁱⁱ  

DHEA is processed by the adrenal cortex and liver into DHEA-Sulfate (DHEA-S). DHEA-S denotes that a sulfate molecule has been added.^iv  DHEA-S is the stable storage form of DHEA as it has an increased half-life in comparison to DHEA.^v  When DHEA is taken orally, it is converted by the body into DHEA-S and enters the bloodstream.^vi

DHEA is used to produce other hormones, including testosterone and estrogen (see figure 1).  

DHEA levels naturally decline with age in both men and women. Individuals 70-80 years of age generally have DHEA levels reduced to 10-20 percent of levels found in young, healthy adults.^vii  In women of premenopausal age, the body produces a total of 6-8 mg of DHEA per day.^viii  Average serum levels of DHEA in healthy adults are 3 ng/mL in women and 2 ng/mL in men.^ix During menopause, most women experience an approximate 4 percent increase in DHEA-S levels which then subside to premenopausal levels by the late menopause stage.^x In addition to age, low DHEA may be a result of chronic stress, the use of certain medications, or another medical condition.  

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How does DHEA work in the body?

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The pituitary gland is often called the “master gland,” and it is located at the base of the brain. It produces adrenocorticotropic hormone (ACTH) in response to corticotrophin-releasing hormone (CRH) from the hypothalamus. ACTH is then released into general circulation in the bloodstream and travels to several sites of action including the adrenals and gonads (ovaries or testes) where it stimulates steroid hormone production.^xi Steroid hormone production begins with cholesterol which is enzymatically processed in cellular organelles, specifically the mitochondria and endoplasmic reticulum, into various steroid hormones.^xii Production of a specific steroid hormone is reliant upon the presence of specific precursors and steroid hormone enzymes. For example, the production of estradiol, a form of estrogen, requires cholesterol to be converted into pregnenolone, then DHEA, followed by androstenedione, then testosterone which is finally converted into estradiol.^xiii  

Figure 1. Pathway of DHEA production and related pathways  

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When are DHEA supplements used for fertility?

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Poor oocyte development, poor ovarian response to hormone stimulation, and diminished ovarian reserve are leading issues experienced by women experiencing infertility.^xiv The age-related acceleration of infertility in women following the age of 37 is characterized by a decrease in hormone production, including a decrease in DHEA and/or testosterone levels; this is accompanied by increased rates of follicular degeneration (atresia) which leads to fewer available ovarian follicles. ^xv Furthermore, women with a low ovarian reserve also often have low antral follicle count and low anti-Mullerian hormone (AMH) levels. DHEA is critical for proper antral follicle development and good oocyte quality; therefore, DHEA supplementation has been suggested as an intervention to improve fertility outcomes in women of increased reproductive age, diminished ovarian reserve, and/or poor oocyte/embryo quality.^{xvi,  xvii, xviii}

In females, the majority of DHEA is converted into testosterone, and testosterone levels are often tested if a fertility specialist suspects that DHEA may be abnormal. Additionally, DHEA-S serum levels may also be tested. If either DHEA or testosterone levels are found to be lower than normal, DHEA supplementation may be recommended by a healthcare provider.

How does DHEA improve fertility?

The exact mechanism of action of DHEA supplementation for fertility-related improvements is unknown. However, researchers hypothesize that DHEA alters the ovarian response to gonadotropin stimulation by increasing levels of androgen and growth factors, which may improve the quality of mature oocytes produced.^{xix, xx}

Additionally, it is known that androgen production and signaling (specifically of DHEA and testosterone) is critical for follicular recruitment and development.^xxi Androgens are also necessary for cell signaling within granulosa and theca follicular cells which aid in the development of healthy, mature oocytes. ^xxii

How successful is DHEA for fertility?

The first documented report of DHEA supplementation for improving fertility in poor ovarian responders was published in 2000.^xxiii  In this small case series, five women diagnosed with poor ovarian response were given DHEA for 2 months prior to ovarian gonadotropin stimulation followed by intrauterine insemination (IUI). All five women experienced an increased ovarian response measured by an increase in the number of follicles (>15 mm) and elevated estradiol concentrations in comparison to previous non-DHEA supplemented cycles.^xxiv Another small-scale case control study published in 2006 compared IVF outcomes in 25 women with diminished ovarian reserve undergoing IVF cycles before and while taking DHEA supplementation. The study found improved fertilization rates and day 3 embryo quality during the IVF cycles with DHEA supplementation compared to the non-DHEA supplemented cycles.^xxv  

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In contrast, other larger research studies have not observed improvement in fertility outcomes. For example, a 2014 randomized, prospective controlled trial from researchers in Turkey investigated the effect of DHEA supplementation (75 mg of DHEA daily for 12 weeks) on the outcome of in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles for women with poor ovarian reserve.^xxvi Overall, this study did not find significant differences in the pregnancy rates (i.e. successful cycle outcomes) between women who used and did not use DHEA-supplementation prior to their IVF cycles.^xxvii

Furthermore, a meta-analysis examined findings from five clinical studies investigating the effects of DHEA supplementation (25 mg, 3 times per day) on cycle outcomes for women undergoing IVF/ICSI cycles.^xxviii Of the five selected studies, four found an increase in clinical pregnancy rates in patients receiving DHEA supplementation,^{xxix, xxx ,xxxi, xxxii} while one study reported no significant increase in pregnancy rates in ..^xxxiii In addition, 4 of the 5 clinical studies reported lower miscarriage rates in patients on DHEA supplementation.^xxxiv These findings suggest that DHEA supplementation prior to ovarian stimulation may improve oocyte quality which could contribute to increased pregnancy rates and decreased frequency of miscarriage. It is important to note however that the meta-analysis is limited by differences in protocols of IVF stimulation and DHEA administration between the five studies.  

Other supplements that have been used for patients with diminished ovarian reserve and/or poor oocyte quality include melatonin, myoinositol, vitamin D, and CoQ10. However, a research study to determine the efficacy of each supplement in comparison to one another has not been conducted. Overall, supplementation of melatonin, myoinositol, vitamin D, CoQ10, or DHEA have all suggested roles in improving oocyte quality, but conclusive results from high quality research studies is lacking.^{xxxv,xxxvi, xxxvii, xxxviii} Individuals interested in adding these supplements to their daily regimen should discuss the topic with their medical providers, because the combination of certain supplements, specifically DHEA and myoinositol, may be counterproductive.^xxxix  

Taking DHEA for fertility

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When considering DHEA supplementation before ovarian stimulation, it is recommended to begin supplementation at least 6-8 weeks before beginning the cycle.^xl  This is due to the process of follicular development, which takes approximately 65 days for a small pre-antral follicle to become a dominant follicle in preparation for ovulation.^xli During this time, oocytes which are believed to benefit the most from DHEA supplementation are at an early stage of follicular development. Most studies have examined the effects of DHEA supplementation on fertility at a dose of 75 mg per day (either as a single 75 mg dose or three 25 mg doses per day).^{xlii, xliii}  

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DHEA is available over the counter in the US at most pharmacies or anywhere vitamins and supplements are sold. Over the counter DHEA is relatively inexpensive at a cost comparable to vitamins. However, as over the counter supplements are not consistently inspected by a reliable source, such as the Food and Drug Administration, to ensure purity, prescription DHEA is also available.  

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Risks and side effects of DHEA for fertility

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Because DHEA can increase androgen levels in the body, individuals with hormone-sensitive cancers should avoid taking DHEA. Patients taking medications for high cholesterol or psychiatric disorders should also not take DHEA as it could alter the effectiveness of these medications. Additionally, women with PCOS, hirsutism, or other medical issues associated with elevated androgen levels should not take DHEA as it may worsen these issues. ^xlivRecommended dosage levels of DHEA should be followed as taking too much DHEA may cause the body to cease naturally making this hormone.^xlv  

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Conclusion

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DHEA supplements present a potential avenue for fertility improvement, particularly in cases of poor ovarian response or diminished ovarian reserve. However, published evidence supporting DHEA use for fertility is limited and inconsistent, and more research studies are needed. Some studies have shown improved pregnancy rates with DHEA supplementation, likely due to its potential positive impact on follicle development. Caution is advised, especially considering potential risks, such as high androgen levels in contraindicated conditions. It's crucial for individuals considering DHEA to consult healthcare providers, discuss appropriate dosages, and weigh potential benefits against possible side effects for a well-informed fertility strategy.

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