Several cases of ovulation and inadvertent pregnancy have been reported following the introduction of hormone replacement therapy (HRT) , in the form of conjugated estrogens or combined oral contraceptive pills, in patients with POI [4–6]. This has prompted the suggestion that exogenous estrogen treatment may be beneficial for improving ovulation and overall fertility, though the exact mechanism is not well understood. One possibility is that exogenous estrogen may lead to suppression of endogenous gonadotropins by downregulation of the luteinizing hormone and follicle-stimulating hormone receptors (LHRs and FSHRs, respectively) [7]. Another proposed mechanism suggests that suppression of endogenous gonadotropins allows synchronization of follicular growth and removal of the suppressing agent leads to rapid follicular development of the follicle with subsequent ovulation [8]. Others have proposed that exogenous estrogen acts by sensitizing granulosa cells to the effects of FSH, thereby leading to ovulation and possible pregnancy [4].

There are many case studies, and few prospective trials, that have utilized exogenous estrogen as fertility therapy for patients with POI [4, 8–11]. One notable randomized controlled trial (RCT) found that physiologic doses of estrogen replacement did not improve the rate of folliculogenesis, ovulation, or pregnancy in patients with POI [12]. Despite these findings, the small sample size and short duration of the study cannot exclude the possibility that estrogen therapy may be of benefit to some patients. The outcome of an earlier retrospective study by Kreiner et al. suggested that a trial of estrogen replacement with close monitoring was warranted prior to moving onto more aggressive therapy, particularly in the setting of secondary amenorrhea and POI [13]. In patients who are interested in pursuing the least invasive method of improving ovarian response, exogenous estrogen treatment in a physiologic dose is a reasonable approach with minimal risk of harm, albeit inconsistent evidence for benefit.

Few studies have attempted to suppress endogenous gonadotropin secretion in patients with POI using GnRH analogues. A small trial using a GnRH antagonist was able to effectively reduce FSH to normal, non-menopausal levels; however, follicular growth was not demonstrated, and gonadotropin levels returned to pretreatment levels following cessation of the therapy, suggesting that POI was not reversed utilizing this method [14]. Another small study investigated the use of GnRH agonist therapy to suppress endogenous gonadotropin secretion; despite concomitant use of exogenous gonadotropins for follicular stimulation, this study failed to produce increased rates of ovulation or pregnancy, despite demonstration of gonadotropin suppression [15]. While limited data exists on the use of these agents for patients with POI, the potential harm of GnRH analogues on overall health, particularly bone health, in this already-hypoestrogenic population suggests they should be used with caution and only in carefully selected patients.

There are even fewer studies analyzing the utility of oral ovulation induction agents for patients with POI. As previously noted, ovulation is intermittent and irregular, though not entirely absent. Utilizing a similar approach to other patient populations with anovulatory cycles, it is theoretically possible to induce ovulation with the same agents. Successful pregnancy has been reported with the use of clomiphene citrate alone [16] or in high doses combined with prednisone and estrogen therapy [17]. There are no reports in the literature on other commonly used oral ovulation induction agents, such as letrozole, for patients with POI that have resulted in successful ovulation induction and subsequent pregnancy. Similarly, there are no prospective studies or RCTs evaluating the efficacy of oral ovulation induction agents of any kind for patients with POI. Although there is a paucity of data, these agents do not pose any theoretical harm to this patient population and may be considered on a limited basis, though no overall benefit has been demonstrated.

A more commonly used approach in patients with POI desiring alternate therapy to IVF with donor eggs is to use exogenous gonadotropins, in combination with other therapies or alone. Multiple studies have investigated the use of human menopausal gonadotropins (hMG) following suppression by cyclic estrogen +/– progesterone HRT, GnRH analogues, or placebo, with minimal success [15, 18, 19]. Though few studies exist demonstrating improvement in ovulation and pregnancy rates, antecedent use of estrogen for suppression followed by hMG for ovarian stimulation has been reported to be a successful treatment in case series from a single center [20, 21]. A more recent double-blinded RCT observed significantly higher rates of ovulation and pregnancy with pretreatment using ethinyl estradiol versus placebo before ovarian stimulation with recombinant FSH (rFSH) [22]. This study was notable in that those receiving pretreatment had an ovulation rate of 32 % vs. 0 % in those receiving placebo, suggesting to the authors that a threshold of FSH ≤15 mIU/mL (induced by the pretreatment of ethinyl estradiol) was necessary to stimulate follicular development by rFSH. These findings suggest that this approach is a reasonable option in POI patients desiring alternatives to IVF.

Another proposed approach to improve ovulation and pregnancy rates in POI is through the use of corticosteroids, either alone or in combination with exogenous gonadotropins. Though there have been reports of successful induction of ovulation [23, 24] and pregnancy [25] using corticosteroids alone, these cases are limited to patients with autoimmune-related POI. In one nonrandomized prospective study, a short course of high-dose prednisone (25 mg four times daily for 2 weeks) was shown to normalize endogenous gonadotropin levels, increase serum estradiol levels, induce follicular growth, and result in subsequent pregnancy in a small proportion of patients [26]. Similar to previous studies, the authors noted that the treatment was most useful in POI patients with autoimmune disease [26]. In a much larger, placebo-controlled, double-blinded RCT investigating the use of dexamethasone along with exogenous gonadotropins for idiopathic POI, the authors found that corticosteroids had no impact on ovarian responsiveness to gonadotropin therapy and that ovulation was not induced in any of the 36 patients enrolled in the study [27]. Due to findings from one case report identifying potential complications that could arise from this therapy, including iatrogenic Cushing syndrome and osteonecrosis of the knee [28], corticosteroid therapy is probably best reserved for those with confirmed or highly suspected autoimmune POI, only after carefully weighing the risks and benefits.

Evidence from growth hormone supplementation to human and rat granulosa cell cultures has demonstrated enhanced production of estradiol and LH receptor formation [29–31]. These findings have prompted some investigators to consider the clinical utility of this option in patients with POI. One case study revealed that the addition of growth hormone-releasing hormone (GHRH) to a regimen consisting of a GnRH analogue and exogenous gonadotropins was able to successfully produce multiple mature follicles in women with POI [32]. Though ovulation may be induced in this manner, no improvement in the pregnancy rate was observed in this study of 42 women. Based on the theoretically plausible potential of growth hormone and GHRH to induce ovulation, this approach may be considered in a research setting, as further studies are warranted.

Supplemental dehydroepiandrosterone (DHEA) was initially reported for use in IVF poor responders with unexplained infertility by Casson et al. after demonstrating increased follicle number and estradiol level with administration [33]. Subsequent studies investigating the use of DHEA in IVF cycles for patients with diminished ovarian reserve have shown increased oocyte yield [34], increased number of fertilized oocytes and higher-quality embryos [35], and increased clinical pregnancy rates [36]. Although the data are limited for DHEA supplementation as a noninvasive fertility treatment for POI, a preliminary study published in 2009 showed significant posttreatment reduction in FSH, increased serum estrogen, and achievement of clinical pregnancy in all five patients [37]. Since that time, the same investigators have published an updated report with additional pregnancy success attributed to DHEA, suggesting that supplementation should be given serious consideration in patients with POI, given its low short-term risk and low cost [38].

Modifications in lifestyle should be considered when counseling patients with POI. Diminished fertility has been well documented in obese and underweight patients, with time to conception increasing twofold and fourfold, respectively [39]. Despite these findings, there is minimal evidence to recommend specific dietary variations to improve overall fertility [40]. Recent animal studies have shown that a high-fat diet may actually accelerate ovarian follicle development and subsequent follicle loss, leading to POI in rats [41]. Though this has yet to be demonstrated in humans, it seems prudent to recommend a low-fat diet to all patients attempting conception. Similarly, regular exercise to maintain a healthy weight and maintain bone health should be encouraged.

Significant research has focused on the use of vitamins and antioxidants to improve clinical pregnancy and live birth rates in women with subfertility and infertility, as reported by a recent Cochrane review [42]. In this review of 28 randomized controlled trials involving 3548 women, the authors compared oral antioxidants, including combinations of antioxidants, pentoxifylline, N-acetyl-cysteine, melatonin, l-arginine, vitamin E, myoinositol, vitamin C, vitamin D plus calcium, and omega-3-polyunsaturated fatty acids, against placebo, no treatment/standard treatment, or another antioxidant [42]. Though these data were not specific to women with POI, there was no association of increased live birth or clinical pregnancy rates with vitamin and/or antioxidant use [42].