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Introduction
Primary ovarian insufficiency (POI), also known as World Health Organization (WHO) type 3 amenorrhea, is defined by the existence of permanent ovarian insufficiency before the age of 40 and occurs in approximately 1% of the female population (1). It is the result of the accelerated decline of ovarian function, leading to hypergonadotropic hypogonadism. Ovarian insufficiency is clinically expressed by the combination of amenorrhea for a period of at least 6 months and elevated follicle-stimulating hormone (FSH) levels (>40 IU/l) (2,3). Further characteristics accompanying this condition are infertility and estrogen deficiency signs (4). There are several causes that can contribute to POI, of which idiopathic cases constitute the largest group (1). In addition, POI can be caused by genetic (such as Turner syndrome), autoimmune, environmental, or iatrogenic factors (5,6). For women with POI, although ovarian function is insufficient to ensure a monthly ovulatory cycle, there is still a small possibility of a spontaneous pregnancy occurring, with studies reporting rates varying from 2.5% to a maximum of 10% (1,7,8). This indicates that complete depletion of the follicle pool may not always be present. Therefore, attention has been given to applying ovarian stimulation to this group of patients in the hope of utilizing the last available follicular reserve and enabling the occurrence of ovulation.
It needs to be recognized however that folliculogenesis is a process that can be manipulated externally only to a limited extent. The continuous transition of follicles from the primordial pool and the subsequent development toward antral stages has classically been considered a process steered primarily by genetic, paracrine, and autocrine factors although the exact interplay of these factors remains to be elucidated. As such, it does not allow much room for manipulation from exogenous endocrine, immunologic, or metabolic factors with the exception of effects at the vascular or cytotoxic level, such as uterine artery embolization, ovarian surgery, or chemotherapy. Rather, it is the later cyclic phase of folliculogenesis that can be manipulated by endogenous signals from the pituitary–ovarian axis or by exogenous FSH and LH. However, depletion of the initial stages of the follicular development pathway will restrict the probability of successful induction of ovulation, and if this pool is (temporarily, but often permanently) absent, the chances of success may be considered futile.
This chapter will discuss evidence-based options for increasing the chances of natural conception through ovulation induction in patients with primary ovarian insufficiency. In addition, potential complications associated with subsequent pregnancy, including after oocyte donation, will be discussed.
Methods for Ovulation Induction
Pituitary Suppression
In the past 30 years, studies have sought to investigate whether pituitary suppression, be it through estrogen replacement or with an agonist of gonadotropin-releasing hormone (GnRH), contributes to a better outcome of ovulation induction in patients with primary ovarian insufficiency. It has been hypothesized that high levels of endogenous FSH in women with POI occupy FSH receptors, rendering them inaccessible for exogenous FSH for ovarian stimulation (9). Thus, lowering endogenous gonadotropins by pituitary suppression could possibly enable stimulation of otherwise resistant ovaries (9).
See Table 21.3 for a summary of clinical studies performed with regard to this method of ovulation induction in patients with WHO type 3 anovulation. A recent case report (10) described an ongoing pregnancy resulting from suppression with a GnRH agonist and estrogen therapy, followed by ovulation induction with exogenous gonadotropins (and luteal support with human chorionic gonadotropin [hCG]). In a crossover trial (11), patients with a normal karyotype POI received a daily dose of 300 μg of desrorelin, a GnRH receptor agonist, followed or preceded by a placebo phase. Estrogen replacement therapy was taken concomitantly. Ovulation was detected in 5 out of 23 women (22%), but the addition of desrorelin was not found to increase the chance of ovulation (11). In 30 women with POI, suppression with buserelin, another GnRH agonist, was compared to placebo with subsequent stimulation with 10,000 IU hCG and 150 IU FSH with increasing doses to 450 IU daily (12). Luteal support was provided by 5000 IU hCG administration every 72 hours. There was no statistical difference between the incidence of ovulation in the treatment and placebo groups although ovulation did occur in three cases in the treatment group compared to none in the placebo group (12).
Summary of Clinical Research Regarding Pituitary Suppression for Ovulation Induction in Patients with WHO Type 3 Anovulation
|
Author Name |
Design |
Patients |
Treatment Regimen |
Results |
|
Nelson et al., 1992 |
CT |
<40 years old, ≥4 months amenorrhea, serum FSH >40 IU/L on at least two occasions N = 23 |
300 μg deslorelin SC/day versus placebo SC/day + 2 mg oral micronized estrogen daily during both phases |
13% ovulation after deslorelin; 9% ovulation after placebo (p > 0.05) |
|
Van Kasteren et al., 1995 |
RCT |
≤38 years old, secondary amenorrhea, FSH >40 IU/L on at least two occasions N = 30 (n = 15 per arm) |
1 mg intranasal buserelin acetate daily versus placebo for 4 weeks + stimulation with 150 IU FSH daily until maximum 450 IU/day |
20% ovulation with buserelin; 0/15 0% ovulation with placebo (p > 0.05) |
|
Buckler et al., 1993 |
PT |
≤36 years old, secondary amenorrhea, FSH >40 IU/L on at least two occasions, serum E2 <100 pmol/L N = 8 |
30 μg EE + 150 μg levonorgestrel daily for 12 weeks |
No ovulation |
|
Anasti et al., 1994 |
CT |
<40 years old, ≥4 months amenorrhea, FSH >40 IU/L on at least two occasions N = 46 |
2 mg oral E2 daily + 5 mg medroxyprogesterone acetate daily (HRT) versus 400 mg danazol daily |
9% ovulatory progesterone level after HRT; 17% after danazol (p > 0.05) |
|
Taylor et al., 1996 |
CT |
<40 years old, ≥2 months amenorrhea, FSH >40 IU/L on at least two occasions N = 32 |
2 mg oral E2 daily versus no treatment |
42% ovulation during estrogen; 39% ovulation during no treatment (p > 0.05) |
|
Tartagni et al., 2007 |
RCT |
<40 years old, ≥6 months amenorrhea, FSH >40 IU/L and E2 ≤25 pg/ml on at least two occasions N = 50 (n = 25 per arm) |
0.05 mg EE 3× daily versus placebo + 200 IU r-βFSH |
32% ovulation with EE; 0% ovulation with placebo (p < 0.005) |
|
Check et al., 1990 |
PT |
≤47 years old, ≤12 months amenorrhea, FSH and LH >35 IU/L N = 100 |
50.70 μg EE daily + hMG 150–375 IU/day |
19% ovulation overall; 2.2% viable pregnancy per cycle |
|
Surrey and Cedars, 1989 |
RCT |
>12 months amenorrhea, FSH >40 IU/L N = 14 |
2.5 mg E2 + hMG (A) 2.5 mg E2 + hMG and 50 μg EE (B) 100 μg GnRH-a histrelin + hMG (C) |
1/6 (17%) ovulation in group C, no ovulation in groups A and B |
Note: CT = crossover trial; EE = ethinylestradiol; HRT = hormone replacement therapy; PT = prospective trial; RCT = randomized controlled trial.
Estrogen replacement therapy is another method of pituitary suppression. In a study with eight women with POI (13), pituitary suppression with oral contraceptives did not lead to subsequent follicular growth or ovulation. The effect of danazol (a sex-steroid derivative) in comparison to estrogen–progestin treatment on ovarian and ovulatory function was studied in a crossover trial (14), showing no statistical differences in ovulation rate. An ovulation occurred in 21% of all included 52 patients (14). Another crossover trial did not find a difference in ovulation or pregnancy rate after estradiol treatment compared to no treatment although high rates of ovulation were reported in both groups (46% in the treatment group compared to 39% in the control group) (15). In a randomized trial with 50 patients, women with POI received ethinyl-estradiol or placebo before receiving 200 IU/day recombinant FSH for ovulation induction (16). The women who received estrogen treatment had a significantly higher ovulation rate (32% versus 0%) following ovulation induction, resulting in pregnancy in half of these cases (4/8) (16).
In a prospective cohort of 100 women with hypergonadotropic amenorrhea (17), gonadotropic suppression was reached through 50 μ g ethinyl-estradiol daily, increasing the dose to 70 μ g in a select group of patients with insufficient pituitary suppression. Subsequent induction using human menopausal gonadotropins (hMG) 150–375 IU/day was studied. Ovulation occurred in 19% of all induction cycles, and the viable pregnancy rate per cycle was 2.2% (17). A randomized trial was conducted in a total of 14 patients with POI (18), in which three treatment regimens were investigated: estrogen-induced suppression followed by stimulation with hMG; estrogen-induced suppression followed by hMG stimulation with concomitant estrogen therapy; and GnRH-agonist induced gonadotropin suppression followed by hMG stimulation. Ovulation occurred in a single patient in the latter group, and no pregnancies were reported (18).
All presented studies, with one exception (17), included patients younger than 40 years old with a history of amenorrhea and/or hypogonadism and FSH determined at two separate time points in a post-menopausal range (>35 mIU/ml). However, the duration of amenorrhea as a criterion for POI diagnosis was not always defined or even differed between studies, ranging from 4 months to >1 year. This difference in applied diagnostic criteria could potentially impact the results and their interpretation. The duration of amenorrhea may have been associated with the degree of the remainder of ovarian reserve, expressed by the permanency level in the number of antral follicles responsive to exogenous FSH or lack thereof, thus greatly influencing the prognosis of ovulation induction.
In summary, pituitary suppression with a GnRH agonist does not seem to ameliorate the outcome of ovulation induction in patients with primary ovarian insufficiency (LOE 1b). Results concerning estrogen replacement therapy are less consistent (LOE 1b). Ovulation rates after ovulation induction vary strongly in patients with POI but have been described to reach up to 42% (LOE 1b). Meta-analysis of the currently available data is not possible due to heterogeneity of the conducted trials (19). Differing diagnostic criteria, use of different treatment protocols, and small sample sizes further limit comparability of results.
Corticosteroid Treatment
For some patients with idiopathic POI, an autoimmune pathophysiology has been suggested (7). Consequently, studies have assessed whether pretreatment with corticosteroids enhances the ovarian response to ovulation induction. See Table 21.4 for a summary of concerning studies. One trial comparing dexamethasone to placebo before treatment with 300 IU hMG was discontinued early due to no ovulation occurring in either the treatment or placebo group (20). In a more recent trial (21), patients were given a GnRH agonist and then randomized to gonadotropin therapy with dexamethasone or gonadotropin therapy with placebo. A 20.7% (6/29) ovulation rate was demonstrated in the dexamethasone group compared with 10.7% (3/29) in the placebo group, which reached statistical significance (21). In an uncontrolled group of 11 women receiving prednisone, an ovulation rate of 18% was found (22).
Summary of Clinical Research Regarding Immunosuppressant Intervention for Ovulation Induction in Patients with WHO Type 3 Anovulation
|
Author Name |
Design |
Patients |
Treatment Regimen |
Results |
|
Van Kasteren et al., 1999 |
RCT |
≥4 months amenorrhea, FSH >40 IU/L N = 36 |
9 mg/day dexamethasone versus placebo + 300 IU hMG/day |
No ovulation |
|
Badawy et al., 2007 |
RCT |
N = 58 |
6 mg/day dexamethasone versus placebo + 3.75 mg/day GnRH-a triptorelin + 300 IU/day hMG |
20.7% ovulation with dexamethasone, 0% with placebo (p < 0.05) |
|
Corenblum et al., 1993 |
PT |
N = 11 |
25 mg 4×/day prednisone |
2/11 (18%) ovulation leading to two viable pregnancies |
Note: PT = prospective trial; RCT = randomized controlled trial.
Thus, in patients with idiopathic POI, adding dexamethasone to a GnRH agonist may increase the likelihood of ovulation after ovulation induction compared to a GnRH agonist alone although further evidence is required (LOE 1b). There is additionally insufficient evidence to conclude whether corticosteroid treatment can increase the chance of spontaneous ovulation and subsequent pregnancy (LOE 1b).
Further Methods of Assisted Conception
In addition to the methods described, a number of adjuvant and alternative strategies have been examined in patients with WHO type 3 anovulation to facilitate conception.
Androgen Intervention
Dehydroepiandrosterone (DHEA) is a precursor of gonadal steroid hormones and consequently plays a role in follicular steroidogenesis. It has additionally been suggested to potentiate the effect of gonadotro-pins on follicle development, making it potentially beneficial for achieving the development of the few potentially remaining follicles in patients with POI. Treatment with DHEA did not improve markers of ovarian reserve or ovulation rate in patients with idiopathic POI in a randomized placebo-controlled trial (23) although the opposite was argued based on several case reports (24). There are currently no results of trials comparing DHEA treatment to placebo with subsequent ovulation induction.
Fertility Preservation
In the event of suspected or predicted accelerated ovarian decline, it may be possible to cryopreserve oocytes, embryos, or ovarian tissue before the complete depletion of the follicle pool. These techniques have, to date, primarily been used in females undergoing treatment for malignant disease with varying pregnancy rates (25), but their applicability to natural fertility decline have additionally been suggested (25). The process of successful fertility preservation has additionally been described in adolescents or women with Turner syndrome. With a greater role for ovarian reserve testing, women at risk for POI may be identified in an earlier stage, thus potentially increasing their options of achieving pregnancy. Initial research is required, however, to validate this technique for this specific group of patients. Animal studies suggest that transplantation of heterologous reproductive tissue may be possible, which would create another opportunity for women with POI, but this awaits further substantiation in human studies.
Oocyte Donation
Oocyte donation with an ongoing pregnancy as a result in a patient with POI was first described in a case report in 1984 (26). This method of conception is currently one of the most frequently used for patients with POI. Pregnancy rates resulting from oocyte donation are comparable, and sometimes superior, to those with other assisted reproduction techniques with rates varying from 20.5% to 58% (27,28). However, offspring from pregnancies following oocyte donation have an approximately 60% greater chance of being born prematurely and with a lower birth weight (27). In addition, maternal pregnancy complications are increased in pregnancies resulting from oocyte donation; increased risks of pregnancy-induced hypertension (31% versus 14%) (29), preeclampsia (17% versus 5%–10%) (28), placental abruption (1% absolute risk) (30), and cesarean section (75% absolute risk) (30–32). The latter results should be interpreted with maternal age as an important confounder in mind. Indeed, a study comparing obstetrical complications of oocyte donation-derived pregnancy in women with POI and women aged above 40 found the complication rate to be significantly higher in the older maternal age group (33). Nonetheless, taking into account the existing risk of obstetrical complications with the addition of the increasing risk of cardiovascular morbidity related to age at menopause (34), patients with POI and a pregnancy following oocyte donation should be considered as high risk. A more extreme risk can become manifest in pregnancy of women with Turner syndrome after oocyte donation due to preexisting cardiac malformations and cardiovascular sequelae associated with this syndrome (35). These considerations should be included in the counseling of women with POI for oocyte donation.
In conclusion, oocyte donation results in definitively higher pregnancy rates than ovulation induction in patients with POI (LOE 3). Pregnancies following oocyte donation are associated with an increased risk of perinatal and maternal complications (LOE 3). There is insufficient evidence to attribute a beneficial effect of androgen precursors on follicle development in the case of ovarian depletion (LOE 1b). Fertility preservation may be considered given the increasing possibility of early detection or prediction of POI (LOE 4).
Conclusion
Patients with POI have a small chance of conceiving spontaneously, making the usage of assisted reproduction techniques an important aspect of achieving pregnancy in this group of women. Studies concerning ovulation induction in these patients are scarce and quite heterogeneous. Another important limitation for the comparability of currently available literature is the use of different stimulation protocols and varying doses and combinations of treatment regimens. The interpretation of results is furthermore impeded due to small sample sizes, leading to underpowered studies. Undergoing treatment protocols for ovulation induction furthermore led to a significantly increased psychological burden in patients with POI (36), warranting a cautionary note in the implementation of treatment.
With the limited data available, it can be concluded that GnRH suppression does not increase ovulation rates. Moreover, currently there are no data indicating that adding DHEA does improve ovulation induction outcome. Inconsistent results are available regarding the use of estrogen replacement therapy in the regimen of ovulation induction, warranting further research. The same holds true for the role of corticosteroid administration in ovulation induction. It is wise to include a critical note, however, as the failure of ovulation induction is inherent to the physiologic state of primary ovarian insufficiency. Due to the limited effect of ovulation induction in patients with POI, oocyte donation is a more commonly used and reliable method for establishing pregnancy. When counseling for the latter option, increased risk of perinatal and maternal obstetric complications should be considered.
Level of Evidence of Statements
|
Statement |
Level of Evidence |
|
Ovulation rates can reach up to 42% following ovulation induction. |
1b |
|
GnRH agonist pretreatment does not improve the results of ovulation induction. |
1b |
|
Estrogen therapy increased ovulation rate in a randomized trial, but this result is contradicted by smaller studies with a lower evidence level. |
1b |
|
Corticosteroid treatment may improve ovulation or pregnancy rates, but further research is required to substantiate this conclusion. |
1b |
|
Dehydroepiandrosterone does not improve the chances of ovulation or endocrine conditions in the ovary. |
1b |
|
Oocyte donation is more effective than ovulation induction for achieving pregnancy, but pregnancies following ovulation induction are more at risk for complications. |
3 |
Grade of Strength for Recommendations
|
Recommendation |
Grade Strength |
|
Patients with POI should be informed about the low probability of achieving pregnancy spontaneously or through ovulation induction. |
B |
|
When opting for ovulation induction, treatment schemes should be individualized due to lacking and contradicting existing evidence. |
B |
|
When considering oocyte donation, patients should be counseled about the increased risk of pregnancy complications. |
C |
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