The decision of whether to administer supplemental parenteral progesterone or human chorionic gonadotropin (hCG), following embryo transfer, to support embryo implantation is by no means clear cut. Ovulation occurs within 38-42 hours of initiation of the spontaneous luteinizing hormone (LH) surge (which can be detected in the blood or urine prior to this event) and/or hCG administered following controlled ovarian hyperstimulation (COH) with gonadotropins.

Usually, a single egg is released with spontaneous (normal) ovulation. Thereupon, each “empty” follicle collapses and converts into a corpus luteum (“yellow body”) which produces both progesterone and estrogen. A similar, but exaggerated response follows IVF where COH with hCG-induced ovulation results in the formation of numerous corpora lutea. The greater the original number of mature follicles, the greater the progesterone/estrogen production is likely to be.

Since COH in women who have absent or abnormal ovulation patterns [e.g., cases of polycystic ovarian syndrome (PCOS)] tends to result in the growth of many more follicles than when performed in controls (i.e., normally ovulating women), it follows that they develop many more corpora lutea and accordingly have exaggerated blood progesterone/estrogen concentrations. The effect of the preovulatory hCG injection is usually sustained for 1-2 weeks exerting a protracted influence on ovarian progesterone/estrogen production. A few days later, provided that embryo implantation takes place, the early trophoblast (root system of the conceptus) begins to produce its own progesterone/estrogen as well as hCG, in ever increasing amounts.

By the 8th week of pregnancy the early placenta provides for all hormonal needs of the developing conceptus. There is compelling evidence to show that hCG augments ovarian (corpus luteum) progesterone release while also promoting growth and development of the trophoblastic “root system” of the conceptus (which eventually will develop into the placenta) as well as estrogen and progesterone production. Since, at the same time, hCG also promotes the production of more hCG, it might be considered a self-propagating hormone. When hCG is administered following egg retrieval and embryo transfer, it is administered by intramuscular injection at a dosage of 5,000 units 3 times weekly, commencing after appropriately rising blood hCG levels signifies that implantation is taking place. Such administration of hCG promotes the release of ovarian and trophoblastic estrogen and progesterone which 6together promote exaggerated secretory changes (decidualization) of the uterine lining, trophoblastic growth, uterine relaxation and adaptation of the reproductive immune response.

By the 8th-9th week of pregnancy, the trophoblast has replaced the ovaries as the dominant source of progesterone and estrogen production. Thereafter there is probably little or no benefit in administering either progesterone or hCG. It follows that a low blood progesterone blood level is much more likely to be the consequence rather than the cause of a failing pregnancy. Thus in such cases the administration of hCG or progesterone in an attempt rescue a failing pregnancy is tantamount to “shutting the gate after the horse has left the stable.”

Most advocates of hCG supplementation recognize that it is risky to administer hCG when a woman inadvertently becomes severely hyper-stimulated. Doing so could exacerbate the condition, placing her at inordinate risk of developing life-endangering complications associated with severe ovarian hyperstimulation syndrome (OHSS). In such cases, it is best to administer progesterone. Another obvious situation where progesterone (rather than hCG) supplementation is called for is in cases where the woman is an embryo recipient (i.e., ovum donation, embryo adoption, gestational surrogacy and frozen embryo transfers). In these cases, ovarian hormonal activity is dormant, rendering any attempt to try to promote ovarian steroid production with hCG, redundant.

Once conversion occurs from reliance upon the corpus luteum to sustain the pregnancy, to self maintenance of the pregnancy by the placental trophoblast, there is probably little benefit to either progesterone or hCG supplementation. This is why after the completion of the 9th week of pregnancy, supplemental hormonal therapy is discontinued.

Progesterone or hCG supplementation likely has significant value in cycles involving pituitary down-regulation with GnRH agonists (e.g. Lupron, Buserelin, Nafarelin, Synarel, Decapeptyl) where there is often luteal phase hormonal deficiency. However, there no conclusive evidence that patients undergoing gonadotropin stimulation without the use of a GnRH agonist or an antagonist would derive benefit from progesterone or hCG luteal phase supplementation. Hormonal supplementation usually involves the daily intramuscular administration of of progesterone and/or vaginal suppositories (comprising estradiol valerate and micronized progesterone) until a blood pregnancy test is performed approximately eight days later (the chemical diagnosis of pregnancy). If the pregnancy test is negative or the plasma hCG levels fail to rise appropriately in the ensuing days, all hormonal support is abruptly discontinued. In most cases Crinone or Endometrin vaginal applications can supplant daily intramuscular progesterone administration.