Ovulation Induction and Controlled Ovarian Stimulation, 2st ed.

1. A Potted History of Ovulation Induction

Roy Homburg1

(1)

Homerton Fertility Centre, Homerton University Hospital, London, UK

Abstract

Since the early 1960s we have been privileged to witness one of the most amazing evolutions in modern medical practice, that of infertility treatment. Up to that time we could do little to help the infertile couple and a consultation usually consisted of some wise nodding of the head and an explanation of the frequency and timing of intercourse. The 1960s, most famous for the introduction and widespread use of the oral contraceptive pill, paradoxically also brought about the possibility to treat anovulation and cure infertility emanating from this cause. Clomiphene citrate was the first agent to restore ovulation and this was soon followed by the extraction and purification of human menopausal gonadotrophins from urine. Today LH and FSH are produced by recombinant technology, shorn of impurities and very safe. The missing link connecting the hypothalamus and the pituitary, gonadotrophin-releasing hormone (GnRH) was elucidated in the 1970s eventually leading to today’s widespread use of GnRH agonists and antagonists. All the milestones in ovulation induction have been accompanied by brilliant technological advances. The advent of IVF, due to the foresight and stubborness of Steptoe and Edwards, and the ensuing technique of intra-cytoplasmic sperm injection (ICSI) have been incredible steps forward. In the last 50 years or so, we have progressed from helplessness to hopefulness for all infertile couples, only few of whom cannot conceive with today’s knowledge and facilities. Can the next 50 years possibly be as exciting for reproductive physicians?

Keywords

Ovulation InductionInfertilityAnovulationClomiphene citrateAnti-oestrogenFSHGonadotrophinsAmenorrheic womenOvarian stimulationIVFICSIIUIGnRHProlactinBromocryptineHyperprolactinaemiahMGLH

From the time I was a medical student in the early 1960s up to the present moment, I have been priviliged to witness one of the most amazing evolutions in modern medical practice, that of infertility treatment. Up to the beginning of the 1960s we could do little to help the infertile couple and a consultation usually consisted of some wise nodding of the head and an explanation of the frequency and timing of intercourse. The 1960s, most famous for the introduction and widespread use of the oral contraceptive pill, paradoxically also brought about the possibility to treat anovulation and cure infertility emanating from this cause.

Clomiphene citrate was tested by Greenblatt et al. [1] in 1961 and found to be a safe and efficient way to induce ovulation. Since then an enormous number have benefitted from the unusual mode of action of this anti-oestrogen in indirectly releasing a spurt of FSH discharge and putting the ovulatory cycle back in correct order. The simplicity and inexpensive nature of this treatment have retained clomiphene citrate until today in its position as the first line treatment for anovulation associated with normal concentrations of endogenous oestrogens.

Around this exiting time, the importance of being able to administer FSH in order to induce ovulation was being realised. This was first achieved in 1958 using human pituitary gonadotrophins by Gemzell [2] and the first resulting pregnancy was reported in 1960 [3]. The classical indication for this treatment was, of course, for those lacking gonadotrophins. Subsequently pregnancies were achieved in hypophysectomized patients, using human pituitary gonadotrophins [45]. This enormous breakthrough sparked the challenge to find a more amenable source for these valuable human gonadotrophins. Menopausal women were known to be excreting them in plenty in their urine and it was Lunenfeld and his group that succeeded in extracting them and inducing pregnancies in large series of amenorrheic women, reported by Lunenfeld [6] and Insler [7] in 1970. On a personal note, I am very proud that both these outstanding researchers were my teachers and instilled in me the enthusiasm for this most fascinating of subjects. Urinary human menopausal gonadotrophins (hMG) have been very widely used up to the present day with extraordinary success, not only for ovulation induction, but also for ovarian stimulation for both IVF and IUI, It is hard to imagine where fertility treatment would be today without them.

The ‘missing link’ in the hypothalamic-pituitary ovarian axis, gonadotrophin releasing hormone (GnRH), was isolated and its structure established in the 1970s [810]. As the structure was a relatively simple decapeptide, a synthetic GnRH soon became available for research and clinical purposes. The synthesis of GnRH may have been relatively simple, but discovering its mode of action and efficient clinical uses took some unravelling. It was Knobil, who in the seventies [11], discovered that GnRH was released from the hypothalamus in a pulsatile fashion and, in order to be effective as replacement therapy, had to be administered in a similar way. This has since been used as the classical treatment for hypothalamic hypogonadotrophic hypogonadism with outstanding success [1213]. However, paradoxically, it was the early ‘failed’ experiments, showing that GnRH, when given continuously, actually suppressed pituitary secretion of gonadotrophins, that led to the widespread use of GnRH agonists and later GnRH antagonists, in so-called controlled ovarian stimulation, in order to prevent premature luteinisation.

Another ‘corner’ of ovulation induction developed in the early 1970s, when prolactin was purified by Hwang et al. [14] and a specific assay was made available [15]. The discovery that high concentrations of prolactin secreted by the anterior pituitary could cause anovulation, prompted the successful search for a prolactin lowering drug. Bromocryptine proved to be very efficient in lowering prolactin concentrations and subsequently allowing the resumption of ovulation [1618]. Since then several other prolactin lowering medications have been developed. They also have the remarkable ability to reduce the size, and often eliminate, micro- and macroadenomata of the pituitary, a common cause of hyperprolactinaemia.

Highly purified urinary hMG is now available and highly purified urinary FSH has also been relatively regularly used. The logistics of urine collection and the suspicion (so far thankfully unsubstantiated) that potentially harmful impurities may exist in urinary preparations, prompted the now widespread use of recombinant human FSH (r-hFSH), produced by recombinant DNA technology. Because of their lack of impurities, these pure FSH preparations can be self-administered subcutaneously and, in addition to their safety, this is a logistically important advantage. It did not take long, using the same technology, before recombinant human LH and hCG became available.

All these milestones in ovulation induction have been accompanied by brilliant technological advances. The advent of IVF, due to the foresight and stubborness of Steptoe and Edwards [19], and the ensuing technique of ICSI [20] have been incredible steps forward.

In the last 50 years or so, we have progressed from helplessness to hopefulness for all infertile couples, only few of whom cannot conceive with today’s knowledge and facilities. Can the next 50 years possibly be as exciting for reproductive physicians?

References

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Palermo G, Joris H, Devroey P, van Steirteghem AC. Pregnacies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet. 1992;340:17–8.PubMedCrossRef


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