11.1.1 Endocrine Control of Follicular Development

Follicle growth from the resting primordial stage until the pre-ovulatory phase takes several months; only the last 2 weeks of this long trajectory are dependent on gonadotropin support (Fig. 11.1) [1]. If maturing antral follicles achieve a distinct stage of development, they are programmed to die, but if serum FSH levels surpass a threshold, these follicles are rescued from atresia, i.e., gain gonadotropin dependence and continue their development [2]. Under normal conditions, elevated FSH levels above the threshold occur during the luteo-follicular transition. The subsequently follicular estradiol secretion inhibits pituitary secretion of FSH, which in turn causes the FSH concentration in the developing cohort follicles to drop below the threshold, the decreased FSH concentrations during the follicular phase are crucial for single dominant follicle selection (Fig. 11.2) [2]. The number of follicles recruited can be increased if endogenous FSH levels are augmented by exogenous gonadotropins or can be reduced if FSH levels are sufficiently diminished [3].

Although of course FSH is the crucial hormone for follicular rescue, LH is necessary for fully functional follicles. The maturing dominant follicle may become less dependent on FSH because of the ability to respond to LH. Basic and clinical experimental evidences indicate that development of ovarian follicles requires a threshold of LH stimulation for adequate follicular development and maturation [4]. The amount of LH required seems to be very low (1–10 IU/L), since only 1% of the LH receptors need to be occupied in order to induce the maximal steroidogenic response from theca cells [5]. LH rise then initiates ovulation, and it is necessary for oocyte mature and follicle rupture [6].

11.1.2 Ovarian Hormones Regulate Gonadotropin Secretion

11.1.2.2 Progesterone Regulates FSH and LH Secretion

Progesterone has multiple effects for regulating gonadotropin secretion [7].

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  First, the high plasma concentration of progesterone, such as is seen in the luteal phase (4–8 ng/mL in humans) enhances the negative feedback effects of estradiol, FSH, and LH secretion being held down to a very low level [8].

  
  
• 
  

  Second, progesterone blocks the positive feedback effect of estradiol on gonadotropin release. The physiologic plasma levels of progesterone, whether achieved by normally functioning corpora lutein or the artificial imposture by progestin implant during the follicular phase of the cycle, prevent the estrogen-induced gonadotropin discharge in intact rhesus macaque [9, 10] (Fig. 11.3). The same blocking effect of progesterone is observed when progesterone is simultaneously administered with estradiol benzoate to castrated women of fertile age with uninterrupted estradiol replacement [11]. This anti-positive feedback of progesterone requires an intact hypothalamus, for the physiological levels of progesterone fail to block the positive feedback in monkeys with hypothalamic lesions on a replacement regimen of exogenous GnRH [12]. Moreover, progesterone does not interfere with the negative feedback inhibition of gonadotropin secretion by estrogen [9].

  
  
• 
  

  Third, progesterone plays a facilitatory role in the initiation of the pre-ovulatory gonadotropin surge after a period of estrogen priming in female monkey, ewes, and human [9, 13–15]. Leyendecker et al. provide experimental evidences in women that progesterone—at low serum levels around 1–2 ng/mL, with a short latency phase of about 3 h, and with adequate estrogen priming—can induce a positive feedback effect in advance, since estradiol benzoate alone induces an LH surge at this stage of the cycle after a considerably longer latency phase (Fig. 11.4) [16, 17]. Also in the rhesus macaque, the positive feedback can, as in women, be augmented and advanced by additional and properly timed administration of progesterone [18].

Thus, the actions of progesterone that could occur at the hypothalamus to enhance or inhibit the GnRH secretion depend on the relative time of the rise of progesterone and estrogen [9, 13–15]. Progesterone exerts its facilitatory effect at the level of the pituitary and its blocking effect at the level of the central nervous system from a series of experiments performed in acyclic, but gonad-intact, rhesus females given exogenous GnRH after hypothalamic lesioning [10, 19, 20].

11.1.3 The Antral Follicles in the Luteal Phase

During the luteal phase, LH and FSH levels are comparatively low and are insufficient to maintain antral follicle development, so follicular atresia occurs. After luteolysis, a new cycle then begins as tonic gonadotropin levels are elevated and progesterone is low. In humans, the follicular phase is about 10–14 days, while in many species such as cow, pig, sheep, and horse, the follicular phase is brief and the major part of follicular growth occurs during the luteal phase of the previous cycle, because FSH and LH levels in these species do not fall to such low levels during the luteal phase [21].

The competence of the antral follicles in normal human ovaries during the luteal phase is not distinguishable from atretic follicles in terms of the number, size range, and steroidogenic activities [22]. The mean number of antral follicles (AFC) was not different in the early-follicular, late-follicular, and luteal phase [23, 24]. Granulosa cells from the luteal phase follicles are responsive to FSH with respect to progesterone and estradiol biosynthetic activity, the aromatase system in the cells from the mid- to late-luteal phase follicles is significantly more responsive to FSH than that in cells from late follicular or early luteal phase follicles [22]. Another evidence about the competence of cumulous oocyte complexes (COCs) retrieved during the luteal phase is that the potential of COCs or in vitro mature (IVM) is comparable whatever the phase of the cycle at which immature eggs in breast cancer patients [25–27]. In addition, some studies show that immature oocytes retrieved during cesarean section (with exposure to high serum progesterone concentrations) are capable of IVM and could lead to live births after fertilization [28, 29]. These materials confirm that during the luteal phase, remaining small antral follicles may be in the early stages of follicular development, suggesting that the ovary could be continuously stimulated during the menstrual cycle.

11.1.4 Waves of Folliculogenesis During the Menstrual Cycle

Contrary to the traditional theory that a single cohort of antral follicles grows only at the early follicular phase, it has been demonstrated that there are two or three waves (namely cohorts) of follicular growth in a single menstrual cycle. Baerwald et al. have shown that 68% of women with regular cycles have two waves of follicular growth during a single menstrual cycle, and 32% of women have three waves through daily ultrasound monitoring (Fig. 11.4) [30, 31].

These waves can be differentiated between major and minor, depending on whether one follicle shows dominance over the others or not, most women having just one major wave with dominance [32]. The follicular wave that emerges in the early to middle follicular phase is ovulatory while the waves emerging in the luteal phase are anovulatory. An elevation in circulating FSH appears to precede the recruitment of each follicular wave during the interovulatory interval in women [30]. The development potential of anovulatory follicles in the luteal phase occurs as a result of progesterone-mediated inhibition of LH secretion to levels that allow follicular development to proceed to the antral or late antral stage, but do not allow the LH surge and ovulation to occur. Anovulatory follicles do not grow as large, on average, as ovulatory follicles. However, a notable number of women exhibited anovulatory follicles that grew to an ostensibly preovulatory diameter [31]. A preliminary trial showed that using pharmacological (recombinant hCG administration) and mechanical (aspiration of dominant follicle) interventions were efficient to induce follicular wave emergence in infertile women [33].

The role of the corpus luteum (CL) in regulating follicular wave dynamics has been studied in women and domestic farm animals (Fig. 11.5). No differences in the size or lifespan of the CL, progesterone, or estradiol secretion were detected in women with two versus three waves or in women with major versus minor waves preceding the ovulatory wave [34]. However, the presence of the CL appeared to influence dominant follicle selection in women with three waves. Luteal regression and progesterone withdrawal occur later in cows with three versus two follicular waves, at which time the viable dominant follicle present goes on to ovulate [35, 36].

It is important to recognize that folliculogenesis is a discontinuous process, independent from the rhythm of the menstrual cycle. The competence of antral follicle in the luteal phase is comparable with those in the follicular phase in previous reports of IVM or in vitro culture. So we presume that the antral follicles in the luteal phase are not atresic, but may be unawakened due to the suppressed FSH/LH, and they have the potential to response to gonadotropin. Follicles can be stimulated to ongoing and gonadotropin-dependent development when the appropriate endocrine signal (i.e., elevated serum FSH levels) is operative [37]. It could, therefore, be speculated that the developing follicles in the luteal phase have the potential to ovulate in the presence of an exogenous LH surge. This is the basic principle to introduce new strategies for ovarian stimulation.

11.2.1 Follicular Phase Ovarian Stimulation

Conventional ovarian stimulation regimens use gonadotropins to promote multifollicular development and GnRH analogue to prevent the LH surge and premature ovulation [40]. The analogue improves the success of IVF cycles by optimizing oocyte retrieval and synchronization of the endometrium. Ovarian stimulation in these protocols starts in the early follicular phase or equivalent. The mild stimulation is performed using a low dose of gonadotropin with or without clomiphene/letrozole; it also begins at the early follicular phase and results with less oocyte yields but with the advantages of patient-friendly and safety [41].

11.2.2 Luteal-Phase Ovarian Stimulation

The luteal-phase ovarian stimulation protocol is originally used for urgent fertility preservation in cancer patients (Fig. 11.6) [42, 43]. Recently they have been tested outside of this context, in normal and poor responders [44–46].

The first live birth of embryos developed from oocytes retrieved following luteal phase stimulation was reported in 2009 [47]. A 40-year-old woman with a 10-year history of primary infertility was given hMG 150 IU and letrozole 2.5 mg from cycle day 3 onwards. Her cycle spontaneously transitioned into the luteal phase beginning on cycle day 10 but the follicles continued growth with hMG stimulation. GnRH agonist 0.1 mg was given for the final stage of oocyte maturation, resulting into four mature oocytes and two top-quality embryos for vitrified cryopreservation (Table 11.1). Two months later, the two embryos were transferred during a natural cycle, creating a twin pregnancy and a favorable delivery. Three-year follow-up showed that the physical and psychomotor development of the twin babies were in the normal range of children conceived naturally [47]. This case report documents favorable outcomes of oocyte development competence following luteal-phase stimulation and opens the door to generalize the successful outcome from luteal-phase stimulation into a routine setting.

Table 11.1

The follicle growth and endocrinological changes in the case of luteal-phase ovarian stimulation

Cycle days	3	4	5	6	7	8	9	10	11	12	13	14	15	16	17	18	19	21
Letr. 2.5 mg/day		+	+	+	+	+	+	+	+	+							Trigger with GnRhA 0.1 mg	OPU
HMG 150 IU/day		+	+	+	+	+	+	+	+	+	+	+	+	+	+	+
FSH (IU/L)	8.53							14.83						9.36			8.83
LH (IU/L)	2.59							6.36						0.61			0.7
E2 (pg/L)	87							56						208			507
P (ng/L)	0.2							2.1						19.2			6
Ultrasound
Follicles
Right	10.4							7									21.8
	8							3.7						10.4			14.6
								3.7						8.9∗2 6.1∗2			11.7 10.3
Left	3.9													5.9			9
														5.9			8.7

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