The normal menstrual cycle in women☆
Introduction
The menstrual cycle of women is tightly controlled by endocrine, autocrine and paracrine factors regulating ovarian follicular development, ovulation, luteinisation, luteolysis, and remodelling of the endometrium. While fundamental reproductive processes are clearly shared between women and our large domestic animals, cycle characteristics, regulatory aspects and research focus can differ widely. For example, cycle irregularities and lack of ovulation are very common in the postpubertal adolescent woman (Golden and Carlson, 2008), but would not have been acceptable in breeding animals, and reduced fertility during reproductive aging is a major research focus in women but not in domestic animals, which are not usually bred late in life.
However, human and animal reproductive physiologists have common interests: (1) the precise detection of the time of ovulation, and (2) understanding determinants of fertility. The first is a challenge to human reproductive medicine, as in menstrual cycles of higher primates ovulation appears ‘hidden’, and menstrual flow does not necessarily indicate normality of cyclicity (Buffet et al., 1998, Harlow, 2000). The second is crucial to achieving economic return from domestic or for conserving wild animal species, but in humans a psychological dimension is added, when couples planning a pregnancy are faced with infertility. Because understanding the menstrual cycle of women will help identify conserved mechanisms underlying ovarian and uterine function, the aim of this review is to discuss what is a normal menstrual cycle, oestrus and fertility; summarise the underlying follicular and luteal function; address the steroid-dependent dynamics of endometrial growth, differentiation and shedding during menstruation; and describe the impact of normal ‘aging’.
Section snippets
The menstrual cycle
Women have a long reproductive lifespan of an average 36 years, from menarche at 8.5 to 13 years to menopause (defined as 1 year of anovulation) at around 51 years (Fig. 1; Aydos et al., 2005, Harlow, 2000, Park et al., 2002). Puberty takes 2.3 years, beginning with breast development followed by pubic hair development and axillary hair growth, and concluding with menarche, the first menstrual period (Park et al., 2002). The ‘textbook’ menstrual cycle (interval from first day of menses to begin
Oestrus
Women have ‘fertile sexuality’ (equated to oestrus) associated with the end of the follicular phase and rising oestradiol before ovulation, which is distinct from ‘extended sexuality’ after ovulation (Gangestad and Thornhill, 2008). During the fertile phase in women features indicative of masculinity and genetic benefit show increased ratings, attraction to extra-pair men increases, while attraction to men who appear sexually faithful decreases. Women's ratings of features indicative of
Fertility
Fertility (clinically diagnosed pregnancy) per menstrual cycle in young women (mean age of 31 years) planning a pregnancy is low (25–30% in the first two cycles) with a high percentage (31%) of subclinical (transient human chorionic gonadotrophin, hCG, rise) and clinical (following a medical diagnosis) spontaneous abortions (Small et al., 2006). The maximum probability of conception to intercourse during the follicular phase is one day before ovulation, however, the fertile-phase spans six
Follicle dynamics
Women ovulate a single DF similar to cows and mares (Fig. 2; Ginther et al., 2001). In reproductive-age women the ovulatory DF emerges at 6 mm diameter on Day 3 of the cycle, 11–12 days before the next ovulation (Ginther et al., 2004), in a cohort of small antral follicles (a follicle wave undergoing ‘cyclic recruitment’, McGee and Hsueh, 2000). Deviation (the time-point from when on DF are morphologically larger than the remaining cohort follicles which will become atretic) occurs 3–4 days
Endocrine changes: the gonadotrophins FSH and LH
As described for cows and mares, a close functional coupling between follicle wave growth, DF selection and FSH exists also in women (Ginther et al., 2001). In regularly cycling women FSH increases at the luteal–follicular transition, beginning 4 days before menses (Fig. 2, Fig. 3; Miro and Aspinall, 2005). Concentrations of FSH achieve maximum levels on the day of emergence of the ovulatory DF followed by a slow decline during the follicular phase (from Days 5 to 13), reaching nadir
Ovarian endocrine function: follicular and luteal secretions
The oestradiol rise in the follicular phase begins after emergence of the ovulatory DF, becomes more rapid following DF selection, and occurs earlier in women with 2 versus 3 follicle waves per cycle (Fig. 2; Baerwald et al., 2003b, Ginther et al., 2005). After ovulation, oestradiol concentrations increase to the mid-luteal phase (Days 7–9 after ovulation) and then decline, and this is due to luteal oestradiol secretion and is unaffected by minor or major anovulatory waves (Fig. 3; Baerwald et
Molecular regulation of dominant follicle selection, ovulation and follicle atresia
Multiple studies have addressed the endocrine, intra-ovarian and intracellular mechanisms regulating follicle growth, differentiation, atresia, ovulation and luteinization in the different monovulatory species including the woman. Key mechanisms involved in dominant follicle selection in the woman, cow and mare appear to be (1) the regulation of the gonadotrophin response, by upregulating LH-receptor and downregulating FSH-receptor expression, (2) ensuring maximum intra-follicular levels of
Molecular aspects of luteal function, regression and rescue by the trophoblast
In contrast to our large animal species luteal progesterone production is dependent on LH throughout the luteal phase, and the result of interactions between steroids, prostaglandins, growth factors and cytokines synthesized by the small and large luteal cells (del Canto et al., 2007, Niswender et al., 2000, Patton and Stouffer, 1991). Corpus luteum regression is independent of the uterus, and is probably due to reduced luteal LH sensitivity rather than systemic reductions in LH pulsatility (
The dynamic endometrium
The endometrium undergoes a steroid-induced monthly cycle of proliferation (regeneration during the follicular phase), differentiation (in the luteal phase) and shedding (menstruation). The upper functional layer is where the activities of proliferation, secretion and degeneration take place, and where the blastocyst implants following conception 7–10 days after ovulation (Strassmann, 1996); regeneration takes place in the lower basal layer (Jabbour et al., 2006). Oestradiol is responsible for
Process of menstruation
Cyclical growth and decline of the endometrium is universal in non-pregnant mammals, but external loss of blood is only seen in old world primates and very few other species (Martin, 2007). The luteal phase places metabolic demands on the woman, and it appears more economical to regenerate and shed than to continuously sustain a fully secretory endometrium (Strassmann, 1996). The cost of menstrual bleeding is considered low, and thus bleeding may only be a side-effect of a blood volume which
Conclusions
Reproduction in the woman contrasts markedly with economically important domestic animal species. High variability in cycle length and ovulation time within the cycle, low fertility per cycle, no overt sign of impending ovulation and the accelerated decline in fertility in our late thirties limit reproductive success. Similarities to the oestrous cycles of cows and mares proposed as model species for women exist and can potentially be exploited to address important questions, such as whether in
Conflict of interest
The authors have no conflict of interest in publishing this review.
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This paper is part of the special issue entitled: Reproductive Cycles of Animals, Guest Edited by Michael G. Diskin and Alexander Evans.
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Present address: Department of Obstetrics and Gynaecology, ANU Research Centre, University College Cork, Cork, Ireland.