The importance of progesterone in achieving + sustaining conception

25 Oct

Progesterone is an important hormone that plays an active part in not only achieving conception but sustaining pregnancy. It is a steroid hormone that is produced by both the adrenal cortex as well as the gonads. The hormone itself is derived from cholesterol and is especially important for the reproductive function of both men to facilitate androgen hormones and spermiogenesis and the women’s menstrual cycle. An increase in progesterone indicates ovulation has taken place and the corpus luteum has been formed. Progesterone is continually secreted by the corpus luteum which supports the thickness of the uterine lining and enables successful implantation of the fertilised egg. After fertilisation and implantation, HcG is secreted to signal to the corpus luteum to continue to secrete progesterone and therefore maintain the pregnancy, preventing menstruation and miscarriage. The ovarian corpus luteum secretes progesterone during the first ten weeks of pregnancy, this is only possible after successful ovulation. After ten weeks, the production of progesterone is taken over by the placenta.

Progesterone supports implantation…

It has a role of importance in the success of implantation due to its impact on the immune system and its ability to suppress and the influence the production of inflammatory mediators in the uterus. A decrease in progesterone results in an increase of inflammation, decreased ability to fight off immunological threats and a myometrium with increased contractility which results in impaired ability for implantation. In addition, it thickens mucus in the cervix creating a barrier to infections and any influence of the immune system that could negatively impact implantation. Increases in progesterone also indirectly regulate neurotransmitter GABAB1 which has been shown by Chen et al. to positively impact embryo implantation and decidualization. GABA receptors play a key role in preparing the uterus for implantation by reducing myometrium contractions whilst maturing the development of the foetus.

It modulates oestrogen…

Progesterone also supports modulation of oestrogen. MMP’s are enzymes that play a key role in the preparation of the endometrium for implantation, and which are proliferated by oestrogen. Progesterone blocks the proliferative effect of oestrogen permitting embryo attachment. Optimal uterine lining is imperative for implantation, as is maintaining the structure of the cervix and positively modifying the mother’s immune response to pregnancy by obstructing production of Th1 cells and blocking cytotoxic T and NK cells to allow the acceptance of the foetus, progesterone facilitates all of this.

It assists in ART…

Progesterone can also be a positive addition to those couples undergoing assisted reproductive cycles by protecting the embryo, producing anti-inflammatory cytokines which can be of paramount importance when luteal phase deficiency is occurring due to follicular damage caused during oocyte retrieval. This can occur due to the greater amounts of FSH used during ovarian stimulation. Luteal phase deficiency is also common when GnRH is used which drives progesterone to remain low, making it essential in supporting early pregnancy outcomes in ART when luteal phase defects have been identified. Luteal phase defects in a natural cycle have also been shown to be a result of low progesterone level, so it’s use here has also been shown to be beneficial for supporting the necessary biological functions to enable a successful pregnancy. 2,8

It maintains a health pregnancy…

Progesterone is considered the most important hormone for maintaining a healthy pregnancy (hence ‘pro-gestation’) and plays an important role in the development and function of the placenta. Once the placenta takes over progesterone production at around week 10-16 (average is week 12), it continues to support the relaxation of the myometrium and the smooth muscle cells it contains until delivery. Loss of progesterone during pregnancy correlates with miscarriage and pre-term labour. Progesterone (P4) has an incredible ability to continue to modulate the immune system function, promoting a tolerant immune environment that gradually reverses prior to the onset of labour. It’s ability to positively adapt the immune system during gestation not only impacts the continuation of the pregnancy but the health of the mother’s immune profile, most notably the balance of T helper type 1 (Th1) and T helper type 2 (Th2), as well as the wellbeing of the foetus. Progesterone has the ability, although not always, to positively balance the immune system to reduce the impact that preexisting autoimmune disorders in the mother can have on the course of pregnancy. The presence of P4 down-regulates immune responses associated with immune-mediated diseases particularly those associated with the activation of CD4+T e.g. rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS).

It can support adverse pregnancy outcomes…

In terms of third trimester risk factors as labour approaches, progesterone has been shown to have a positive impact on reducing hypertensive disorders in pregnancy as well as protect against pre-term labour. A 2023 systemic review and meta-analysis found ‘first-trimester initiated vaginal micronized progesterone may reduce the risk of HDP and pre-eclampsia.’ The review found a ‘moderate-certainty evidence that first-trimester initiation of vaginal progesterone treatment resulted in a 29% reduction in HDP rates and a 39% reduction in pre-eclampsia rates’. Early progesterone initiation is critical. The need to investigate the pathways in which progesterone may prevent placental maladaptation is also critical.

It supports cervix health…

Progesterone can also have an important and positive impact on late-term pregnancy in that pre-term labour onset can be supported with progesterone therapy when evidence of cervix shortening is present. Whilst more research is required about optimal dose, timing and administration of progesterone in those women that have a history of spontaneous preterm birth, vaginal progesterone reduces preterm birth risk prior to 34 weeks by 9.4%. In multiple births the research is mixed, with some suggesting progesterone administration in twin pregnancies can significantly reduce preterm birth <33 weeks’ gestation and other study trials having no statistical conclusion due to the cohort size.

References

(1) Cable, JK. Grider, MH. (May 2023). ‘Physiology, Progesterone’. [Online]. Available at:

https://www.ncbi.nlm.nih.gov/books/NBK558960/ (Accessed 10 October 2024)

(2) Hechtman, L. (2019). ‘Clinical Naturopathic Medicine’. Second Edition. Australia: Elsevier. Available at: https://bookshelf.health.elsevier.com/reader/books/9780729585750/epubcfi/6/2[%3Bvnd.vst.idref%3Did_cover]!/4/2 (Accessed 10 October 2024)

(3) Chen, W. Zhang, Q. Wang, H. et al. (2021). ‘Unique and independent role of the GABAB1 subunit in embryo implantation and uterine decidualization in mice’, Genes & Diseases, 8 (1), pp. 79-86. [Online]. Available at: https://www.sciencedirect.com/science/article/pii/S2352304219300418 (Accessed 10 October 2024)

(4) Shah, NM. Imani, N. Johnson, MR. (2018). ‘Progesterone Modulation of Pregnancy-Related Immune Responses’, Front Immunol, 9. [Online]. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020784/

(5) Świątkowska-Stodulska, R. Berlińska, A. Stefańska,K. (2022). ‘Endocrine Autoimmunity in Pregnancy’, Front Immunol, 13. [Online]. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9277138/

(6) Hellberg, S Raffetseder, J. Rundquist, O. el al. (2021). ‘Progesterone Dampens Immune Responses in In Vitro Activated CD4+ T Cells and Affects Genes Associated With Autoimmune Diseases That Improve During Pregnancy’, Immunol. 12. [Online]. Available at: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.672168/full

(7) Melo, P. Devall, A. Shennan, AH. (2023). ‘Vaginal micronized progesterone for the prevention of hypertensive disorders of pregnancy: A systematic review and meta-analysis’, BJOG, 131 (6), pp. 727-739. [Online]. Available at: https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/1471-0528.17705

(8) Ulubaşoğlu, H. Bakay, K. Yavucan, A. (2024). ‘Vaginal Progesterone Gel versus Intramuscular Progesterone for Luteal Phase Support in Suboptimal Responders Undergoing Assisted Reproductive Cycles’, CEOG, 51 (9). [Online]. Available at: https://www.imrpress.com/journal/CEOG/51/9/10.31083/j.ceog5109196

(9) RANZCOG. (2010). ‘C-Obs 29b Progesterone: Use in the second and third trimester’. [Online]. Available at: https://ranzcog.edu.au/wp-content/uploads/2022/05/Progesterone-Use-in-the-second-and-third-trimester-of-pregnancy-for-the-prevention-of-preterm-birth.pdf