European Review for Medical and Pharmacological Sciences 2020; 24: 9104-9111 Dehydroepiandrosterone supplementation improves ovarian reserve and pregnancy rates in poor responders M.D. OZCIL Department of Obstetrics and Gynecology, Mustafa Kemal University School of Medicine, Hatay, Turkey Abstract. – OBJECTIVE: We investigated Introduction whether DHEA supplementation had an impact on ovarian reserve parameters and pregnancy A trend for postponement of pregnancy due rates in patients with poor ovarian response to marriage at an older age has increased the ra- (POR) and primary ovarian insufficiency (POI). PATIENTS AND METHODS: A total of 34 tios of infertile couples in society. The decrease people, 6 patients with POI and 28 patients with in ovarian reserve with advancing age has led to POR, were included in the study. The patients new approaches in the treatment of infertile pa- in the POR group consisted of two different tients. The main causes of premature ovarian ag- groups: diminished ovarian reserve (DOR) and ing and diminished ovarian reserves are; endo- premature ovarian failure (PMOF). Patients in metriosis, genetics, stress, obesity, past mumps the POI and POR group were given 50 mg DHEA infection, chemotherapy, radiotherapy, smoking, supplementation daily for 5 months. The prima- ry outcome was to determine spontaneous clini- alcohol use, pesticides, chemical toxins, auto- cal pregnancy rates. The monthly changes in the immune diseases, idiopathic, ovarian induction serum hormone levels and AFC were recorded agents, systemic diseases, long-term analog or for five months. AMH levels were also measured antagonist use and diabetes mellitus. Many treat- before and after treatment. ment modalities have been attempted to improve RESULTS: The total follow-up time was 152 the reduced ovarian reserve. Dehydroepiandros- cycles. The number of pregnancies during the follow-up period was 9. The ratio of pregnan- terone (DHEA) has been used in approximately cies to the number of patients was 26.5% and 25% of in vitro fertilization (IVF) centers for the the rate per cycle was 5.9%. While 8 of 9 preg- treatment of infertile patients with poor ovarian nancies resulted in a live birth, one resulted in response (POR)1. a miscarriage. The rate of abortion was 11.1%. DHEA is naturally found in the Jerusalem ar- The mean AFC was 0 to 5 before treatment. tichoke, and in the human body is secreted by the Following DHEA administration, a significant adrenal gland (zona reticularis) and from the the- increase was detected in 30.8% of the patients. There was an increase in AMH levels after ca interna cells of the ovaries. DHEA has a role DHEA, but this was not significant. The live as precursor hormone in the synthesis of estra- birth rate and pregnancy rate per cycle were diol and testosterone2. It has a weak androgenic significantly higher in POR patients than those effect. After peaking between the ages of 20 and in POF. Patients with POF had no pregnancy. 30, DHEA levels decrease by about 2% each year Although the PMOF patients were younger than down to 10-20% of the peak at around the age of the DOR patients, the rate of pregnancy (36% 3 vs. 29%), and pregnancy rates per cycle (8.5% 80 years . The purpose of DHEA supplementa- vs. 6.35%) were higher in the DOR group. The tion is to replace DHEA in patients with reduced rates of live birth were the same in the PMOF ovarian reserves. The substitution of DHEA may and DOR groups (29% vs. 29%). correct the substrate pool of steroidogenesis. An- CONCLUSIONS: Oral DHEA supplementation drogens have been shown to increase steroidogen- improves both ovarian reserve and pregnancy esis and insulin-like growth factor 1 (IGF-1) in rates in women with POR. primate ovaries4,5. IGF-1 levels in preantral and early antral follicles have been reported to be ele- Key Words: vated in DHEA-treated mouse ovaries6. Casson et DHEA, POR, POI, Ovarian reserve, Pregnancy 7 rates. al reported that DHEA supplementation was use- ful in intrauterine insemination (IUI) treatment 9104 Corresponding Author: Mustafa D. Ozcil, MD; e-mail: [email protected] Dehydroepiandrosterone supplementation improves ovarian reserve in patients with poor response to ovarian stimula- considered with the presence of a fetal heartbeat. tion. This benefit of DHEA is attributed to an in- Serum Follicle Stimulating Hormone (FSH), Lu- crease in serum-free IGF-I concentration, which teinizing Hormone (LH), and Estradiol (E2) levels in turn increases the gonadotropin response in the were measured at baseline and monthly during target organ7. In 2005, it was shown that oocyte 5 months after DHEA supplementation. Fast- production was increased, and 9 healthy embry- ing blood samples of the patients were collected os were obtained after DHEA supplementation in with venipuncture. All samples were centrifuged a 43-year-old IVF patient with DOR8. However, at 1500 g for 10 min, at 4°C. Serum FSH, LH, several studies have reported conflicting results E2 and progesterone levels were evaluated with of DHEA supplementation on ovarian reserve the electrochemiluminescence method (ADVIA markers and pregnancy outcomes in infertile pa- Centaur XP, Siemens Diagnostics, Los Angeles, tients with diminished ovarian reserve (DOR) or CA, USA). The AFC (2-10 mm follicles) as deter- premature ovarian failure (PMOF)9-15. The aim of mined by transvaginal ultrasonography (General this study was to investigate the effect of DHEA Electric RTX 200, Boston, MA, USA). supplementation on ovarian reserve parameters Patients were excluded if they had a history of and pregnancy rates in infertile patients with a malignant or borderline ovarian tumor, meta- POR or primary ovarian insufficiency (POI). bolic disease, a chromosomal disease in either of the partners, male factor infertility, or hysterosal- pingography revealing defective female genita- Patients and Methods lia. Genetic disorders such as Turner syndrome, patients using alkylating agents or radiotherapy, A total of 34 women, 6 patients with POI and patients who underwent ovarian surgery, patients 28 patients with POR, were included in the study. with hyper or hypothyroidism, patients with type The patients in the POR group consisted of two dif- I diabetes, those with Cushing disease or Addison ferent patient groups: diminished ovarian reserve disease, excessively obese cases and extremely (DOR) and premature ovarian failure (PMOF). weak cases were also not included in the study. Patients who met at least two of the Bologna cri- The study was approved by the Ethics Committee teria were accepted as poor ovarian reserve16-18. of Mustafa Kemal University School of Medicine These criteria were: (1) advanced maternal age (Protocol No: 2017/157-27.10.2017-183). Informed (≥40 years) or other risk factors for poor ovarian consent was obtained from all the patients. reserves; (2) history of previous POR (≤3 oocytes with conventional over stimulation protocols); and Statistical Analysis (3) an abnormal ovarian reserve test [i.e., an antral Statistical analyses were performed with the follicular count: AFC, < 5-7 follicles or < 0.5-1.1 SPSS 20.0 software (IBM Armonk, NY, USA). ng/ml of Anti-Mullerian Hormone (AMH)]. Se- Data were shown as mean ± standard deviation rum AMH levels were analyzed by using AMH (SD) values or percentage. The effect of DHEA on Gen II ELISA kit (Beckman-Coulter, Inc., Brea, ovarian reserve parameters was evaluated. Per- CA USA). Values are expressed in ng/mL. Prima- centages of serum hormone levels before and after ry ovarian insufficiency (POI, primary ovarian treatment were compared using the Paired t-test. failure, POF) was defined as a 4-month period of Percentages of AFC in the groups were compared amenorrhea, serum FSH levels > 40 IU/L at one- using the Chi-square test. The pregnancy outcome month intervals, and a decrease in sex steroids in was compared according to age, infertility status women younger than 40 years. Patients in the POI and the type of ovarian pathology. A p ˂0.05 was and POR group were given 50 mg DHEA (Inter- considered as statistically significant. pharm, Konya, Turkey) supplementation daily for 5 months. This time interval was chosen because of early follicular growth induced by DHEA oc- Results curs within et least 2 months of treatment. The primary outcome was to determine spontaneous The demographic and follow-up characteristic clinical pregnancy rates. Pregnancy was evalu- of 34 participants during DHEA supplementa- ated in all patients with serum β-HCG levels af- tion is summarized in Table I and Figure 1. The ter menstruation delay. Patients with a positive mean age of the patients was 35.8 ± 7.6 years. 24 β-HCG result underwent TV-USG at 6 weeks af- out of the 34 patients were primary infertile. The ter the last menstruation. Clinical pregnancy was remaining ten patients were secondary infertile. 9105 M.D. Ozcil Table I. General characteristics and pregnancy outcomes of patients with POR and POF given DHEA supplementation. Age (year, mean± SD) 35,8 ± 7.6 Infertility status Primary infertility (n, %) 24 (70.5%) Secondary infertility (n, %) 10 (29.5%) Type of ovarian dysfunction POF (n, %) 6 (17.6%) PMOF (n, %) 14 (41.1%) DOR (n, %) 14 (41.1%) Total follow up period (cycles, n) 152 Total number of pregnancies achieved and percent based on number of patients (n, %) 9 (26.4%) Total number of pregnancies achieved and percent based on number of cycles (n, %) 9 (5.9%) Total number of pregnancies delivered in term (n, %) 8 (23.5%) Total number of abortions (n, %) 1 (11.11%) POF: Primary Ovarian Failure; PMOF: Premature Ovarian Failure; DOR: Diminished Ovarian Reserve; SD: Standard Deviation; N: Patient number. The total follow-up time of patients was 152 cy- ber of mean AFCs ranged from 1 to 5. Following cles. The total number of pregnancies during the DHEA administration, a significant increase was follow-up period was 9.