Primary ovarian insufficiency (POI), commonly referred to as premature ovarian failure (POF), is defined as the cessation of ovarian function with follicle-stimulating hormone (FSH) concentrations exceeding 40 IU/L before 40 years of age, resulting in amenorrhea, infertility, and other systemic consequences (e.g., cardiovascular diseases and osteoporosis) because of estrogen deficiency [1]. POI is first brought to light by Fuller Albright in 1942 [2], and it affects approximately 1% of women at the age of 40, 0.1% of women at the age 30, and 0.01% at the age 20 [3]. About 76% of POI patients developed after normal puberty and establishment of regular menses [4].

Multiple causes contributing to POI include environmental factors, genetic background, autoimmunity, metabolism, and iatrogenic factors. However, the cause of POI remains undetermined in most cases [5]. Familial POI research showed that 4–30% of all subjects with POI had a familial form [6], which implied a genetic predisposition to POI. We found that ESR1 PvuII and XbaI polymorphisms were correlated with POF, while no association was found for FST, adiponectin gene, and FMR1 premutation to POF [7–10]. In addition, we conducted a meta-analysis to investigate the association between gene variants and POF. The results showed that BMP15 538A, FMR1 premutation, and INHA 769A (in Asians alone) may indicate susceptibility to POF [11]. Interestingly, a novel gene HFM1 mutation was identified in Chinese POI patients [12]. A recent study reported that variations in BMP15 gene dosage have a relevant influence on ovarian function and can account for several defects in female fertility. The modulation of BMP15 action may have interesting pharmacological perspectives, and the analysis of BMP15 may become a useful marker in IVF procedures [13].

Women with POI extremely rarely ovulate and achieve pregnancy spontaneously [14], so infertility is an important issue in POI/POF patients. Numerous treatment protocols for follicular development and ovulation induction have been tested in patients with POI, and none have been shown to be effective [15]. There are various therapeutic interventions before IVF included clomiphene citrate, gonadotropins, estrogens, GnRH analogues, oral contraceptives, corticosteroids, dehydroepiandrosterone (DHEA), or a combination of these [16]. Therefore, oocyte donation is chosen to be a unique opportunity in the treatment of infertility with POI, although about 5–10% are able to obtain pregnancy after the POI diagnosis.

Oocyte donation and IVF has been used as an aid for conception for young women with POI for over 20 years. In other words, the IVF with donor eggs is a practical treatment strategy and a hope for women with POI to become a mother. Generally, the cryopreserved embryos have been employed for ovum donation in POI with a high pregnancy rate of 30% per transfer [17]. In the reproductive center of our hospital, the First Affiliated Hospital of Nanjing Medical University, analysis of 89 oocyte donation IVF-ET cycles showed that implantation cycle rate was 91.0% (81/89), biochemical pregnancy rate was 40.7% (33/81), and clinical pregnancy rate was 37.0% (30/81).

As all known, the first successful IVF treatment was performed in a natural cycle [18]. Generally, natural cycles in IVF have been used for patients who have shown a poor response in at least two previous attempts with gonadotropin stimulation [19]. Some studies showed that [19, 20] the developed follicles of poor responders in natural cycles may produce fewer oocytes but oocytes of better quality than their hyperstimulated ovaries [21]. Furthermore, it is also less expensive and more time-efficient, avoids most of the risks and complications of ovarian stimulation, spares the endometrium from the adverse effects of ovarian stimulation, and is more psychologically friendly to the IVF patients [21]. Concerning the natural cycle in IVF used for the patients with POI/POF, there has been only one study carried out in Japan, in which they reported four women with POI who achieved pregnancies resulting from intrauterine insemination in combination with cyclic estrogen/progesterone therapy and close monitoring of follicle development [22].

Indeed, POI patients, whether or not they desire pregnancy, should be treated with a combination of estrogen and progesterone hormone replacement therapy (HRT) to minimize the bone loss, decrease the risk of cardiovascular events, and relieve the vasomotor flushes and vaginal dryness [14]. Meanwhile, pregnancy may occur while a woman is undergoing estrogen and progestin therapy, suggesting that this might be a method to improve fertility in POI women. Theoretically, estrogen replacement therapy might improve ovulation rates in women with spontaneous POI by reducing the associated chronically elevated serum LH levels to normal [23]. Interestingly, Naredi et al. [24] reported that the pregnancy rate in women after an oocyte donation cycle was 40% in subjects who received HRT prior to their cycle, while only 25% conceived in the non-HRT group, although the difference did not statistically significant.

We reported two cases of POI who achieved pregnancy by modified natural cycle IVF in reproductive center of the First Affiliated Hospital of Nanjing Medical University as follows.

A 29-year-old patient, a nulligravida with 4-year history of primary infertility with POI, was diagnosed in our reproductive center. Her karyotype is 46, XX, without a history of chemotherapy or radiotherapy, but she had received a laparoscopic cystectomy for bilateral endometrial cysts at 25 years. Her basal serum levels of FSH, LH, and E2 were 48.3, 10.6 IU/L, and 125.9 pmol/L, respectively. Only one AFC in the left ovary and one in the right ovary, separately, can be seen by trans-vaginal ultrasonography. She had undergone a total of five natural or mild stimulation IVF cycle treatments in past three years. For her successful cycle, which occurred at 32 years of age, the serum levels of FSH, LH, and E2 were 16.1, 1.5 IU/L, and 235.3 pmol/L, respectively, on day 3 of a natural cycle. On day 9 of the cycle, there was a single follicle with an average diameter of 15.3 mm and serum levels of LH, E2, and P were 24.3 IU/L, 1248.7 pmol/L, and 4.84 ng/L, respectively. Ovulation was triggered with 0.1 mg of Diphereline. After 36 h, one MII oocyte was retrieved and fertilized by ICSI. Eight-cell embryo was transferred on day 3 after fertilization. Pregnancy was confirmed on day 14 after embryo transfer. The patient has achieved ongoing pregnancy, and she delivered her baby at 37 week’s gestation.