https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(96)05291-9.pdf

Factors that affect outcome of in-vitro fertilisation treatment

Relaxin has vital physiological roles in pregnant rats, mice, and pigs. Relaxin promotes growth and softening of the cervix, thus facilitating rapid delivery of live young. Relaxin also promotes development of the mammary apparatus, thus enabling normal lactational performance. The actions of relaxin on the mammary apparatus vary among species. Whereas relaxin is required for development of the mammary nipples in rats and mice, it is essential for prepartum development of glandular parenchyma in pregnant pigs. During pregnancy relaxin also inhibits uterine contractility and promotes the osmoregulatory changes of pregnancy in rats. Recent studies with male and nonpregnant female rodents revealed diverse therapeutic actions of relaxin on nonreproductive tissues that have clinical implications. Relaxin has been reported to reduce fibrosis in the kidney, heart, lung, and liver and to promote wound healing. Also, probably through its vasodilatory actions, relaxin protects the heart from ischemia-induced injury. Finally, relaxin counteracts allergic reactions. Knowledge of the diverse physiological and therapeutic actions of relaxin, coupled with the recent identification of relaxin receptors, opens numerous avenues of investigation that will likely sustain a high level of research interest in relaxin for the foreseeable future.

Relaxin's physiological roles and other diverse actions.

There are seven relaxin family peptides that are all structurally related to insulin. Relaxin has many roles in female and male reproduction, as a neuropeptide in the central nervous system, as a vasodilator and cardiac stimulant in the cardiovascular system, and as an antifibrotic agent. Insulin-like peptide-3 (INSL3) has clearly defined specialist roles in male and female reproduction, relaxin-3 is primarily a neuropeptide involved in stress and metabolic control, and INSL5 is widely distributed particularly in the gastrointestinal tract. Although they are structurally related to insulin, the relaxin family peptides produce their physiological effects by activating a group of four G protein-coupled receptors (GPCRs), relaxin family peptide receptors 1-4 (RXFP1-4). Relaxin and INSL3 are the cognate ligands for RXFP1 and RXFP2, respectively, that are leucine-rich repeat containing GPCRs. RXFP1 activates a wide spectrum of signaling pathways to generate second messengers that include cAMP and nitric oxide, whereas RXFP2 activates a subset of these pathways. Relaxin-3 and INSL5 are the cognate ligands for RXFP3 and RXFP4 that are closely related to small peptide receptors that when activated inhibit cAMP production and activate MAP kinases. Although there are still many unanswered questions regarding the mode of action of relaxin family peptides, it is clear that they have important physiological roles that could be exploited for therapeutic benefit.

https://www.physiology.org/doi/pdf/10.1152/physrev.00001.2012

Relaxin Family Peptides and Their Receptors

BACKGROUND: It is well known that miscarriage risk increases with age. However, studies usually investigate only maternal age effects. We investigated both maternal age and paternal age effects on miscarriage risk to provide insight into this frequent reproductive failure. METHODS: The last planned pregnancies (n 3174) that ended in a birth or miscarriage were analysed in a retrospective population-based study on women aged 25–44 years in Denmark, Germany, Italy and Spain. Maternal and paternal ages were analysed together, using a single variable 'couple age' in a multivariate logistic regression analysis, with couples composed of a woman and a man both aged 20–29 years forming the reference group. RESULTS: After adjustment for various factors (e.g. reproductive history, country), we found that the risk of miscarriage was higher if the woman was aged 35 years, as has already been reported in a number of studies. However, the increase in risk was much greater for couples composed of a woman aged 35 years and of a man aged 40 years. Potential source of bias (especially 'reproductive compensation') are discussed. CONCLUSIONS: The risk of an adverse pregnancy outcome is highest if both partners are advanced in age.

/pdf/paternal-age-and-maternal-age-are-risk-factors-for-30ih51yrgp.pdf

Paternal age and maternal age are risk factors for miscarriage; results of a multicentre European study

Although the hormone relaxin was discovered 80 years ago, only in the past 5 years have the receptors for relaxin and three other receptors that respond to related peptides been identified with all four receptors being G-protein-coupled receptors. In this review it is suggested that the receptors for relaxin (LGR7) and those for the related peptides insulin-like peptide 3 (LGR8), relaxin-3 (GPCR135), and insulin-like peptide 5 (LGPCR142) be named the relaxin family peptide receptors 1 through 4 (RXFP1-4). RXFP1 and RXFP2 are leucine-rich repeat-containing G-protein-coupled receptors with complex binding characteristics involving both the large ectodomain and the transmembrane loops. RXFP1 activates adenylate cyclase, protein kinase A, protein kinase C, phosphatidylinositol 3-kinase, and extracellular signaling regulated kinase (Erk1/2) and also interacts with nitric oxide signaling. RXFP2 activates adenylate cyclase in recombinant systems, but physiological responses are sensitive to pertussis toxin. RXFP3 and RXFP4 resemble more conventional peptide liganded receptors and both inhibit adenylate cyclase, and in addition RXFP3 activates Erk1/2 signaling. Physiological studies and examination of the phenotypes of transgenic mice have established that relaxin has roles as a reproductive hormone involved in uterine relaxation (some species), reproductive tissue growth, and collagen remodeling but also in the cardiovascular and renal systems and in the brain. The connective tissue remodeling properties of relaxin acting at RXFP1 receptors have potential for the development of agents effective for the treatment of cardiac and renal fibrosis, asthma, and scleroderma and for orthodontic remodelling. Agents acting at RXFP2 receptors may be useful for the treatment of cryptorchidism and infertility, whereas antagonists may be used as contraceptives. The brain distribution of RXFP3 receptors suggests that actions at these receptors have the potential for the development of antianxiety and antiobesity drugs.

https://pharmrev.aspetjournals.org/content/pharmrev/58/1/7.full.pdf

International Union of Pharmacology LVII: Recommendations for the Nomenclature of Receptors for Relaxin Family Peptides

In a retrospective study, the relationship between endometrial thickness and pregnancy rate has been studied in 59 ovum recipient women. Transvaginal ultrasound assessment of endometrial thickness was performed immediately prior to ovum transfer: 19 pregnant recipients had a mean endometrial thickness of 10.24 mm +/- 2.63 SD, 40 nonpregnant recipients had an endometrial thickness of 8.62 mm +/- 3.49 SD (t = 1.805, P = 0.0382). Only two pregnancies occurred in 15 recipients with an endometrial thickness < 7.5 mm, and none when the endometrial thickness was < 5 mm. Our results indicate that endometrial thickness is related to the functional receptivity of the endometrium.

Endometrial thickness: a predictor of implantation in ovum recipients?

This study was performed to evaluate the relative contribution of oocyte and uterine factors to the age-related reduction in fecundity. The pregnancy and miscarriage rates in women receiving donated oocytes were compared to those in women using their own oocytes in in-vitro fertilization (IVF) and gamete intra-Fallopian transfer (GIFT) procedures. Oocyte donation with embryo transfer was performed on 241 women in 371 cycles; 116 of these women became pregnant (48% per patient and 31.5% per cycle) of whom 40 (35%) miscarried, giving a live birth rate of 20.5%. Assisted conception, in the form of IVF/GIFT procedures, was performed on 1331 women using their own oocytes in 2194 cycles; 627 of these women became pregnant (47% per patient and 28.7% per cycle), of whom 228 (36%) miscarried, giving a live birth rate of 18.2%. Neither the age of the donor nor the age of the recipient was related to pregnancy rate. The age of the donor, however, was directly related to the miscarriage rate. On the other hand, the age of patients undergoing IVF/GIFT was inversely related to the pregnancy rate and directly related to the miscarriage rate. In women of 40 years or over, the overall pregnancy and live birth rates were significantly higher and the miscarriage rate was significantly lower in the group receiving donated oocytes compared to the group using their own oocytes. In summary, we suggest that the age-related decline in fecundity is associated with the age of the oocytes rather than the age of the uterus.

Age, pregnancy and miscarriage: uterine versus ovarian factors.

Eighty-two patients had 100 cycles of oocyte donation from 68 donors resulting in 27 clinical pregnancies. The source of donated oocytes was 42 fertile volunteers and 26 patients from the assisted conception programme. The pregnancy rate was significantly higher when intra-Fallopian transfer was performed (36%; 21/59), compared with intrauterine transfer (15%; 6/41). The pregnancy rate following fresh gamete/embryo transfer (39%; 15/39) was slightly higher than for frozen embryo transfer (20%; 12/61). The age of the recipient significantly affected the pregnancy rate. The pregnancy rate was 50% in the 25-29 years age group and steadily dropped to 9.7% in the 45-49 age group. The pregnancy rate in patients with primary ovarian failure (50%; 8/16) was significantly higher than in patients with secondary ovarian failure (18%; 9/50). The pregnancy rate was significantly greater when parous donors (33%; 23/69) were used compared with non-parous donors (13%; 4/31). The number of gametes/embryos transferred significantly affected the pregnancy rate regardless of the treatment used. If one or two gametes/embryos were transferred, the pregnancy rate was 11% compared with 33% if three to four embryos were transferred. The age of the donors did not affect the pregnancy rate. The majority of the donors were under the age of 35 years. The best results (50% per cycle) were therefore achieved using gametes from parous donors and transferring three to four oocytes fresh to the Fallopian tubes of a young recipient.

A report on 100 cycles of oocyte donation; factors affecting the outcome

Relaxin levels in ovum donation pregnancies

The attitudes of anonymous volunteer donors (n = 20) and infertile patients who were undergoing treatment in an IVF programme and who donated oocytes (n = 15) towards the donation, the recipient, the potential children conceived, the recording of information and their experience of the procedures were sought by posted questionnaires. All donations were made for altruistic reasons and no payments other than expenses were made. Both groups agree that donors should not be paid and they both deny any connection with the child resulting from their donation. The majority in both groups also did not object if their eggs were donated to unmarried single women and they did not wish to meet with the recipient. The majority of both groups would however agree to donate to known recipients. Over 80% had told others of their donation and a similar number in the volunteer group held no objection to the recipients knowing their name whilst only 40% held the same view in the patient donor group (17/20 versus 6/15 P less than 0.02). The feelings of the groups was also different in relation to their desire to know if a child was born from their eggs. Eighty five per cent in the volunteer group (17/20) would like to know the outcome and only 40% (6/15) of the patient donor would want to know the outcome, P less than 0.02. Although greater than 50% in both groups experienced side effects, 60% of volunteers and 90% of patient donors expressed a willingness to donate eggs again.(ABSTRACT TRUNCATED AT 250 WORDS)

A. Kirkland

Papers

Endometrial thickness: a predictor of implantation in ovum recipients?

Age, pregnancy and miscarriage: uterine versus ovarian factors.

A report on 100 cycles of oocyte donation; factors affecting the outcome

Relaxin levels in ovum donation pregnancies

A comparison of the attitudes of volunteer donors and infertile patient donors on an ovum donation programme