Treatment of WHO 3

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Treatment of WHO 3

Annelien C. de Kat, Scott M. Nelson, and Frank J.M. Broekmans


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).

TABLE 21.3

Summary of Clinical Research Regarding Pituitary Suppression for Ovulation Induction in Patients with WHO Type 3 Anovulation

Author Name



Treatment Regimen


Nelson et al., 1992


<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


≤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


≤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


<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


<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


<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


≤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


>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).

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