The luteal phase is defined as the period between ovulation and either the establishment of a pregnancy or the onset of menses two weeks later [1]. Following ovulation, the luteal phase of a natural cycle is characterized by the formation of a corpus luteum, which secretes steroid hormones, including progesterone and estradiol (E2).

Allowing infertile couples to fulfill their longings of having children, assisted reproductive techniques (ART) have progressed rapidly day by day since 1978, the time when they were first introduced. Advances and improvements in the existing techniques and interventions in medicine (ovulation induction, embryo culture techniques and the selection criteria, culture media, and advanced techniques for embryo manipulation) lead the achievements in this area to progress further every day.

Deficiencies in luteal hormonal dynamics have been clearly documented during controlled ovarian stimulation [1]. Disruptions to the physiological secretion of luteinizing hormone (LH) by the anterior pituitary affect optimal corpus luteum (CL) function warranting some form of luteal phase support (LPS) in order to maintain optimal endometrial receptivity in stimulated cycles.

Clomiphene (clomifene) citrate (CC) and follicle-stimulating hormone (FSH) have traditionally been considered the two main modalities used for ovarian stimulation (OS). However, many adjuncts have been used to maximize the convenience and effectiveness of these two agents, often specifically targeted to subsets of women undergoing stimulation. Most of these adjuncts are not officially approved for these indications. Therefore, educators and practitioners must take it upon themselves to assess the evidence supporting their use, and make treatment recommendations and decisions accordingly. We have outlined in an editorial in Fertility and Sterility a process to aid in this endeavor [1]. Decisions are based not only on randomized clinical trials (RCT), but also on other basic science and clinical evidence supporting their use.

Controlled ovarian stimulation (COS) is an important step during in vitro fertilization (IVF) treatment that aims to produce sufficient follicles and oocytes to achieve pregnancy. Despite recent progresses in assisted reproductive technology (ART), a poor ovarian response (POR) remains one of the most challenging issues for reproductive clinicians [1]. The incidence of POR during COS has been reported to range from 5.6 percent to 35.1 percent depending on differences in the definition of poor response [1–4]. Patients with POR have higher cycle cancellation rates, lower pregnancy rates, and heavier financial burden [4–6]. In this chapter, we discuss the classification and treatments of POR.

Induction of ovulation is one of the major advances in the treatment of subfertility in the last decades. One aspect of ovulation induction that required attention is the occurrence of a premature luteinizing hormone (LH) surge before the leading follicle reaches the optimum diameter for triggering ovulation by human chorionic gonadotrophin (hCG). It was reported that premature LH surge occurs in a significant number of patients undergoing ovulation induction [1]. Such premature LH surge prevents effective induction of multiple follicular maturation for in vitro fertilization (IVF) and resulted in a significant cancellation of IVF cycles [2].

Half a decade ago, we witnessed the culmination of much of what we comprehend today in classical ovarian endocrinology and physiology [1;2], human embryology [3] as well as clinical ovarian ultrasonography [4]. Much of the former was based upon the development of (radio-)immunoassays that could reliably detect low concentrations of hormones in body fluids, including the peripheral circulation. This meant that correlations of hormone concentrations and specific physiological events could be determined with precision, leading to many advances in clinical practice and drug development. The biological control of all these physiological elements is, of course, gonadotropin-releasing hormone (GnRH), whose decapeptide structure was elucidated by Andrew Schally and colleagues in 1971 [5], for which he was awarded his share of the Nobel prize in 1977. His co-prize winners were responsible for the pioneering of immunological competitive binding dilution assays, which underwrote all these developments.

The lack of ovulatory cycles may be considered as a major problem for women seeking pregnancy. This is reflected by the fact that about 20 percent of couples visiting a fertility clinic with an unfulfilled wish to conceive present with anovulation [1]. Clinical manifestation of anovulation is oligomenorrhea (intermenstrual period > 35 days) or amenorrhea (intermenstrual period > 6 months). Although ovulation may occur in oligomenorrhea, the longer the time period between menstruations the smaller the chance of that cycle being ovulatory. Classification of anovulatory patients may be performed using the criteria of the World Health Organization (WHO) as determined by Rowe et al.

The number of retrieved oocytes is one of the major parameters by which the intensity of ovarian stimulation is estimated. While conventional stimulation protocols in in vitro fertilization (IVF) are designed to obtain maximum oocytes yields, they have often been associated with increased risk of complications, increased costs derived from higher gonadotropin dosage, and lower embryo quality. For these reasons, physicians have introduced a milder approach to ovarian stimulation, focusing on a more patient-friendly and safe method, while attempting to improve IVF outcomes. Typically, the strengths of mild stimulation include: reduced mean number of days of stimulation, smaller total amount of gonadotropins, smaller mean number of oocytes retrieved balanced by possibly better embryo quality, decreased treatment discomfort, and reduced risk of complications. However, to date there are still unanswered questions about the possibility that a milder approach to ovarian stimulation is clinically superior to conventional regimens.

Ovulation induction using stimulation drugs has now been in practice for over 40 years. Until the introduction of ultrasound, monitoring of follicular growth was a difficult task. Transvaginal ultrasound is now the routine for ovulation induction monitoring. Transvaginal probes have a much higher frequency reaching 4–9 MHz, and have wider angles up to 180º and depths that could reach 16 cm, facilitating the procedure of monitoring.

Traditionally, controlled ovarian stimulation in women undergoing assisted reproductive technology (ART) treatment was designed in a standardized fashion taking into account the age and body weight of the patient. A standardized treatment protocol has been described as a “one-size-fits-all” approach that does not take into account inter-individual differences.

The reproductive cycle requires complex interactions and feedback between gonadotropin-releasing hormone (GnRH), the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and the ovarian sex steroid hormones estrogen and progesterone. To improve the success rate of in vitro fertilization-embryo transfer (IVF-ET) by optimizing oocyte retrieval, controlled ovarian stimulation (COS) has been widely performed. Exogenous gonadotropins were used to achieve supraphysiological levels during the follicular phase to override the process of dominant follicle selection and enable multiple follicular recruitment, which lead to a rapidly increasing serum estradiol level and induce a premature LH surge. GnRH agonist (GnRHa) and GnRH antagonist were used to prevent the premature LH surge and premature ovulation [1]. In 2003, based on ultrasonographic studies, Baerwald et al. demonstrated that multiple cohorts or “waves” of 2–5 mm follicles were recruited continuously during a menstrual cycle, including in the luteal phase [2;3].

Human reproduction is highly inefficient, and that is why it has been widely observed and documented since the ancient civilizations. Fertility has been a main concern along the history. Greeks already described “the best time for fruitful intercourse” [1] understanding that women are not fertile all days of the menstrual cycle. The poor effectiveness of the human species continuity is due to a fair number of factors involved to achieve a successful pregnancy: quality and quantity of sperm, ovum and embryo quality, chromosomal abnormalities, and the capability of the endometrium to harbor the embryo among others. The synchrony between the embryo development and the endometrium maturation must work as perfectly as the gear of a watch.

Polycystic ovarian syndrome (PCOS) is one of the most prevalent endocrinopathies affecting 5 to 10 percent of women of reproductive age [1;2]. Characteristic clinical features of PCOS include menstrual irregularity such as oligomenorrhea/amenorrhea and signs of hyperandrogenemia including hirsutism, acne, and/or obesity. The syndrome was first clearly described by Stein and Leventhal in 1935 [3]. While the primary etiology remains poorly defined [4], insulin resistance with compensatory hyperinsulinemia is a prominent feature of the condition and appears to be an underlying cause of hyperandrogenemia identified in both lean and obese women [5]. Hyperinsulinemia promotes increased ovarian androgen biosynthesis in vivo and in vitro [6;7]. It also decreases sex hormone-binding globulin production in the liver [8], which results in the increased bioavailability of free androgens and exacerbates the signs of androgen excess.

Conventional ovarian stimulation protocols intend to yield as many oocytes and embryos as possible to try to maximize the success of an in vitro fertilization (IVF) program. In reality, however, a series of studies over the last few years observed that live birth rates (LBRs) do not increase after a certain number of retrieved oocytes [1–3]; some studies even found a decline in LBRs when the number of oocytes was in excess of 18 [4] or blastocyst numbers above 5 [5]. Although the cumulative LBR keeps rising over and above the number of oocytes/embryos that maximizes per cycle live birth, the incidence of ovarian hyperstimulation syndrome (OHSS) and venous thromboembolism (VTE) also escalate in a parallel fashion [2;3;6]. A recent study, by restricting the stimulation dose to 150 IU/day, found only nine oocytes or four embryos optimizing the fresh cycle LBR [7].