In the field of reproductive medicine, the concept of timing is of paramount importance. Indeed, the majority of consultations that take place between a reproductive medicine specialist and a patient will include some mention of time and its implications for treatment and outcomes.

As well as examining some of these time-related concepts, this overview will consider the challenges faced by healthcare professionals working in the care of infertility.

FERTILITY AND AGEING

One peculiarity of the human ovary is the cessation of activity at the age of menopause, a demise of function which is not seen in the testes. The total pool of functional follicles within the ovaries, having been formed by the 20th week of fetal life, continues to undergo depletion through successive waves of follicular growth and atresia, until final exhaustion.¹

This loss is exponential, with initial numbers estimated at 6–7 million oocytes declining to 500,000 by puberty. In fact, during a female’s entire reproductive lifespan, only around 400 oocytes are capable of ovulation.¹

Fertility declines with age across all populations in both men and women. However, the effects are more pronounced in women. It has been shown that, for women, the chance of conception decreases significantly after the age of 35 years.²

Although sperm parameters in men can begin to show a decline from the age of 35, population studies have shown that fertility per se does not appear to lessen before approximately 50 years. At the age of 50–54, fertility rates were found to be 73% of those of men in their early 20s.³

IMPACT ON FERTILITY TREATMENT

The impact of ageing on fertility treatment outcomes is quite evident when referring to birth rate outcome registries. When examining Human Fertilisation and Embryology Authority data for 2017 birth rates for all women having in vitro fertilisation (IVF) in the UK, one can observe a clear trend. Comparing fresh IVF cycles only, the birth rate is 30% in the under-35 age group per embryo transfer, 23% for those aged 35–37, 15% for the 38–39 age group and as low as 4% for women aged 43–44.⁴

A similar pattern is seen in IVF treatment cycles performed in the USA. The organisation responsible for reporting outcomes, the Society for Assisted Reproductive Technology, stated in 2017 that there was a 40.5% singleton live birth per cycle started for under 35s, dropping to 30.3% in the 35–37 age group, 18.7% in those aged 38–40, and as low as 9.1% for women aged 41–42.⁵

This age-related decline in fertility should be considered when deciding when one should begin assessment for couples. As infertility can be defined as the failure to conceive after 1 year of unprotected vaginal sexual intercourse or exposure to sperm,⁶ early clinical assessment can be considered after 6 months without conception for women aged over 35, as per NICE guidelines.⁷

INEFFICIENCY OF HUMAN CONCEPTION

Even in the most optimal conditions, the chance of human conception is no more than 30–40% within each menstrual cycle.⁸ In the general population (which covers all ages and includes people with fertility problems), it is estimated that 84% of women would conceive within 1 year of regular unprotected sexual intercourse. This rises cumulatively to 92% after 2 years and 93% after 3 years.⁹

For conception to be possible, intercourse must take place at a time when both the oocyte and the sperm are at maximal viability. This ‘fertile window’ has traditionally been considered to be the 6-day interval ending on the day of ovulation. This window can be ascertained by analysing the intermenstrual interval, using urinary ovulation predictor kits to look for the luteinising hormone (LH) surge or monitoring changes in body temperature or cervical mucus.

Data have consistently shown that peak fecundability (the probability of pregnancy per month) occurred if intercourse took place within the 3-day interval ending on the day of ovulation.¹⁰

One particular study of women who self-reported their menstrual cycles to be generally ‘regular’ showed that the likelihood of conception increased during this fertile 3-day window. (These women responded ‘yes’ to the question ‘Is the length of time between your periods about the same each cycle and therefore regarded as regular?’) The probability of clinical pregnancy increased from 2% on cycle day 7 to 9% on cycle day 13 and decreased to less than 2% by cycle day 21.¹¹

Cycle fecundability also increases with the frequency of intercourse during the fertile window.¹² A retrospective study, which analysed almost 10,000 semen specimens, demonstrated that semen quality, sperm concentrations and motility remained normal even with daily ejaculation, putting to rest the common misconception held that frequent ejaculations reduce male fertility. Furthermore, prolonged abstinence intervals of 5 days or more can adversely affect sperm parameters.¹³

MONITORING OVULATION

The timing of peak fertility can vary significantly, even in women having regular cycles. Predicting ovulation can be frustrating for couples attempting conception, and there is no substantial evidence¹⁴ that monitoring by any of the purported methods can increase fecundability. Applying technology in the form of tracking applications has gained popularity over the years. However, relying solely on these tools to time intercourse should be exercised with caution. A recent study using data collected from such applications revealed some interesting insights into ovarian cycle physiology. The authors analysed key characteristics from more than 600,000 menstrual cycles. The results revealed significant variability in cycle and follicular phase lengths.¹⁵

Determination of ovulation by the app was achieved retrospectively using an algorithm based on basal body temperatures, menstrual cycle parameters and positive LH tests.

An LH surge results in triggering a follicle to rupture. The surge begins approximately 28–48 hours before follicle rupture, and peak LH levels are noted at 12 hours prior to rupture. Corpus luteum formation follows follicular rupture, and progesterone secretion begins. The thermogenic effect of progesterone results in a distinct rise of 0.2–0.3°C following ovulation, allowing basal body temperatures to be used as a marker for the luteal phase of the menstrual cycle.¹⁶

The data demonstrated that cycle length differences were noted primarily as a result of a variable follicular phase. The mean follicular phase length was 16.9 days. The authors concluded that cycle length alone may not suffice to identify the fertile window, and tracking supplemental physiological parameters is imperative.

One large study demonstrating this point showed that changes in cervical mucus, namely increased volumes of slippery and clear mucus, were able to predict a higher chance of conception as well as or better than basal body temperature or urinary LH monitoring.¹⁷

THE IMPLANTATION WINDOW

Following fertilisation of an egg, the tiny embryo – positioned in the oviduct – has to undertake a journey of mammoth proportions. Upon reaching the uterus, the embryo engages in a complex interaction with the maternal interface. This two-way communication results in physical contact between the embryo and the endometrium and subsequent implantation.

Long range signalling to the pituitary-ovarian axis regarding the implanted embryo results in maintenance of the corpus luteum and a sustained progestogen environment.

During the mid-secretory phase of the menstrual cycle, rising progesterone levels lead to the creation of a nutritionally rich glandular support network for the embryo. The endometrium undergoes significant histological changes, signalling the opening of the implantation window.

The implanted embryo, now at the blastocyst stage, is able to establish its own circulation as well as provoking maternal circulatory changes.

This intricate process depends entirely on the time-dependent opening of a receptive phase in the cycle, known as the implantation window. For an embryo to thrive, early development and transport to reach the uterus in time for this receptive window are paramount. Beyond this point, the uterus will resist any further attempts at attachment.

TIMING IN ASSISTED REPRODUCTIVE TREATMENT

Understanding the time-critical nature of human conception underpins the creation of the protocols that are used in assisted reproductive technology.

This can range from tailoring the dose and duration of follicle-stimulating hormone administration in order to achieve the optimal number of oocytes for fertilisation, to the timing of an embryo transfer following adequate luteal phase support with progesterone in an IVF cycle. Successful outcomes depend on our ability to perform the steps of treatment within optimal time frames.

Often the fine margins that distinguish a successful IVF cycle from an unsuccessful one hinge on time. With our greater understanding of the implantation window, both in the context of natural conception as well as in the application of this knowledge to assisted conception cycles, the field of reproductive medicine has seen continuing strides towards greater success for our patients.

Kugajeevan Vigneswaran, King’s Fertility and King’s College Hospital NHS Foundation Trust, London

Sesh Kamal Sunkara, Division of Women’s Health, Faculty of Life Sciences and Medicine, King’s College London

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