Premature ovarian failure and dehydroepiandrosterone

Leonidas Mamas M.D., Ph.D. Eudoxia Mamas BSc.

Neogenesis IVF Centre, 3 Kifisias Ave, 151 23 Marousi, Athens, Greece

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Corresponding author:

Leonidas Mamas M.D., Ph.D.

Neogenesis IVF Centre, 3 Kifisias Ave, 151 23 Marousi, Athens, Greece

FAX: +30 210 6836090

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Fertility and Sterility Journal (www.fertstert.org)

DHEA  proved to be significantly effective in the treatment of POF  in the first five cases of an ongoing study. All patients showed an improved gonadotrophin hormonal profile and, more importantly, all achieved pregnancy.

Since the first patient with premature ovarian failure (POF) referred to our Centre was successfully treated with dehydroepiandrosterone (DHEA) giving birth to a healthy baby, all subsequent POF patients followed the same treatment protocol. Receiving very encouraging  results (FSH level was decreased in all first five patients and all achieved pregnancy) it was decided to study the DHEA action in depth for a reasonable length of time and a larger number of patients in order to confirm the effectiveness of this particular therapeutic regime. 

Ovarian failure is a natural consequence of the ageing process. Unfortunately, a great number of women experience premature ovarian failure (POF) while still in the reproductive age. POF is a condition characterized by amenorrhoea or oligomenorrhoea due to the early reduction of ovarian follicles (1), along with hypergonadotrophic and hypooestrogenic hormonal changes that affect women before the age of 40. Women suffering from POF present major difficulties with fertility and conception (2).
     More often, POF presents with secondary amenorrhoea (3) and affects 1 to 5% of women (4). A great number of aetiological factors have been associated with POF including genetics, autoimmune disease, iatrogenic and viral. In the majority of POF cases however, a cause cannot be clearly identified and are referred as idiopathic POF (3).
     The causes of POF are vast and therefore treatment options are equally numerous but share one common target; pregnancy. The list of therapies includes clomiphene citrate, gonadotrophins, oestrogens, GnRH analogues, oral contraceptives, corticosteroids, combinations of the above or, if nothing else succeeds, egg donation. With these treatments 6.3 % of all women suffering from POF become pregnant (2).  
Dehydroepiandrosterone (DHEA) is an endogenous steroid that originates from the zona reticularis of the adrenal cortex and the ovarian thecal cells, in women (5). Its production starts with the conversion of cholesterol being an important step in the formation of testosterone first and then to estradiol in peripheral tissues. It is therefore, an important prohormone for ovarian follicular sex steroidogenesis (6).
    The concentrations of DHEA in women remain high during the reproductive years and then, progressively, decrease. Many hypotheses have been made on how DHEA promotes fertility. It is known that DHEA is an important step in the production of testosterone, oestradiol and androstenedione. If, however, the level of DHEA is low, the concentration of  these hormones are expected to be also low (5). Furthermore, DHEA is believed to increase follicular insulin-like growth factor – 1, that can promote the gonadotrophin effect (7). Moreover, in rat models, DHEA has been shown to promote a polycystic environment in the ovaries with increased levels of active oocytes and decreased atretic effects. A similar response has been documented in women exposed to androgens (8).
     In our IVF Centre, the first patient, that agreed to follow DHEA treatment was a 37 year old woman, with FSH 102 mIU/mL, referred to us by an endocrinology clinic for egg donation, in April 2006. In the preparation process, oestradiol valerate was given to the patient in order to improve the endometrial thickness. However, the response was very poor, so it was decided to administer DHEA instead, in an attempt to increase the level of endogenous oestrogens. Surprisingly, two months in the DHEA treatment, the patient reported her first period in nine months of amenorrhoea and three months later the level of FSH had dropped to 18,9 mIU/mL  (Case 1, Table I). The patient conceived naturally and gave birth to a healthy baby boy.
    Following this successful outcome, it was decided to apply the same protocol to other patients with POF. The treatment consisted of two 25mg micronized dehydroepiandrosterone dietary supplement capsules per day (BIO-DH Natural Organics Laboratories inc. USA). The decision to stop, continue, decrease or increase the DHEA administration was based on various factors; FSH, LH and E2 levels, the presence of period, or conception.
   So far, a further four cases with POF were treated with DHEA. Case 2, was a Greek woman living in Switzerland who was referred in our Centre for egg donation.  She suffered of 12 months amenorrhoea with FSH 112 mIU/mL  when she visited our centre and agreed to try DHEA as a final step before egg donation. Within one month on DHEA, her FSH had dropped to 30 mIU/mL  and two months later, her period reappeared. Natural conception occurred on the third month of treatment, currently  being   27 weeks pregnant.
    Case 3, was a troubled patient with POF and a history of two unsuccessful IUIs and one IVF. She responded relatively quickly to DHEA, with her FSH decreased to 12.5 mIU/mL,  just two months in therapy, while her LH levels remained high (70 mIU/mL) despite the drop of FSH. Following the reappearance of periods, the patient underwent intrauterine tuboperitoneal insemination (IUTPI) (9). She is now 14 weeks pregnant.
    Case 4, a 38 year old patient, visited our Centre following four failed IVF attempts. She agreed to start DHEA therapy in order to reduce the levels of FSH. Approximately, two months into the treatment she conceived naturally. Unfortunately, at 7 weeks gestation the patient had a missed abortion. The FSH level increased within one month since the patient’s missed abortion. She is currently willing to restart DHEA therapy.
    Case 5 proved to be slightly more complicated. Her starting FSH was 45 mIU/mL. Similarly to all the other cases already treated with DHEA, she began with two 25 mg BIO – DH capsules daily. However, three months into the treatment, her FSH levels had dropped only slightly, even though she reported regular periods. With the patient’s consent it was decided to increase the dose of DHEA to three 25 mg capsules daily. A month later, FSH levels were reduced to 14 mIU/mL   and the patient is now 11 weeks pregnant.
    As back as 1998, the best, if only, chance of women with POF to achieve pregnancy was egg donation (10). DHEA proved to be an effective first step treatment of POF. The 50mg daily dose was sufficient in most cases, except one, who received 75mg daily instead, due to poor response to 50mg. DHEA administration was continued for two to 6 months and stopped when pregnancy was ensured, initially by pregnancy test, followed by ultrasound scan.
    Literature offers quite a few  studies presenting   DHEA administration as a treatment to increase the oocyte quality and quantity.  Moreover, DHEA increases the production of endogenous oestrogens. Our first experience of the effectiveness of DHEA for the treatment of POF was a poor responder to oestradiol valerate. Following DHEA therapy, the endometrial thickness was increased and normal periods reappeared along with a reduction of the levels of FSH.
    The same therapeutic regime was successfully used to the second case. The patient shared many similarities to the first one: same hormonal profile, age and was also referred for egg donation. Sharing their experience in a specialised internet IVF forum, DHEA treatment became known to a number of women with the same problem and eventually some of them visited our Centre.
    All patients with POF that agreed to receive DHEA therapy had already undergone full hormonal and thyroid function tests. The longest period of DHEA administration in the above cases was approximately six months. None of the patients wished to stop receiving DHEA and no side effects were reported.
    Within the last year, DHEA was been implemented in our Centre for the treatment of POF. The positive results were an unexpected surprise to us, so much so, that we decided to study the treatment further with a larger number of patients and in a longer period of time. Through this correspondence we wanted to present these promising initial findings of an ongoing study in our IVF Centre.

References:

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6.        Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE. Dehydroepianrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod 2000;15:2129 – 2132. 

7.        Casson PR, Santoro N, Elkind-Hirsch K, Carson SA, Hornsby PJ, Abraham G, et al. Postmenopausal dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density lipoprotein: a six-month trial. Fertil Steril 1998;70:107–10.

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9.        Mamas L. Comparison of fallopian tube sperm perfusion and intrauterine tuboperitoneal insemination: a prospective study. Fertil Steril 2006;85:735 – 740.

10.     Anasti JN. Premature ovarian failure. Fertil Steril 1998;70:1 – 15.