Midcycle administration of a progesterone synthesis inhibitor prevents ovulation in primates.

Abstract

Progesterone receptors appear in granulosa cells of preovulatory follicles after the midcycle gonadotropin surge, suggesting important local actions of progesterone during ovulation in primates. Steroid reduction and replacement during the gonadotropin surge in macaques was used to evaluate the role of progesterone in the ovulatory process. Animals received gonadotropins to induce development of multiple preovulatory follicles, followed by human chorionic gonadotropin (hCG) administration (day 0) to promote oocyte (nuclear) maturation, ovulation, and follicular luteinization. On days 0-2, animals received no further treatment; a steroid synthesis inhibitor, trilostane (TRL); TRL + R5020; or TRL + dihydrotestosterone propionate (DHT). On day 3, ovulation was confirmed by counting ovulation sites and collecting oviductal oocytes. The meiotic status of oviductal and remaining follicular oocytes was evaluated. Peak serum estradiol levels, the total number of large follicles, and baseline serum progesterone levels at the time of hCG administration were similar in all animals. Ovulation sites and oviductal oocytes were routinely observed in controls. Ovulation was abolished in TRL. Progestin, but not androgen, replacement restored ovulation. Relative to controls, progesterone production was impaired for the first 6 days post-hCG in TRL, TRL + R5020, and TRL + DHT. Thereafter, progesterone remained low in TRL but recovered to control levels with progestin and androgen replacement. Similar percentages of mature (metaphase II) oocytes were collected among groups. Thus, steroid reduction during the gonadotropin surge inhibited ovulation and luteinization, but not reinitiation of oocyte meiotic maturation, in the primate follicle. The data are consistent with a local receptor-mediated role for progesterone in the ovulatory process.A hallmark of reproductive cycles in female mammals is the process of ovulation. A triad of well-coordinated events occurs locally within the ovarian follicle during the periovulatory interval. First, the follicle-enclosed oocyte undergoes both nuclear and cytoplasmic maturation to render it capable of fertilization. Second, the mature, preovulatory follicle ruptures-i.e., ovulates-to release the oocyte. Third, luteinization of the steroidogenic somatic cells of the follicle, known as theca and granulosa cells, results in morphological differentiation to form the corpus luteum. The ovulatory process is initiated by the surge of pituitary gonadotropins, mainly luteinizing hormone (LH), that occurs at midcycle (1). Other factors produced within the follicle during the periovulatory period, such as metabolites of arachidonic acid (2), peptides (3), and steroids (4), likely play a role in LH-induced ovulation, at least in rodent models. Understanding the ovulatory process is obligatory for development of therapies to alleviate infertility due to ovulatory dysfunction, such as the luteinizing unruptured follicle syndrome (5) in women, as well as alternative methods for controlling fertility by...

Estradiol regulation of progesterone synthesis in the brain

“…First, high levels of estradiol are absolutely essential (Brom and Schwartz, 1968;Ferin et al, 1969;Labhsetwar, 1970). Second, estradiol induced progesterone receptors (PR) in the hypothalamus are needed (Chappell et al, 2000;DePaolo, 1988;Hibbert et al, 1996;Mahesh and Brann, 1992;SanchezCriado et al, 1994;Snyder et al, 1984). Third, preovulatory progesterone is also essential for the gonadotropin surge (DePaolo, 1988;Hibbert et al, 1996;Mahesh et al, 1992;Micevych et al, 2003;Remohi et al, 1988).…”

“…Second, estradiol induced progesterone receptors (PR) in the hypothalamus are needed (Chappell et al, 2000;DePaolo, 1988;Hibbert et al, 1996;Mahesh and Brann, 1992;SanchezCriado et al, 1994;Snyder et al, 1984). Third, preovulatory progesterone is also essential for the gonadotropin surge (DePaolo, 1988;Hibbert et al, 1996;Mahesh et al, 1992;Micevych et al, 2003;Remohi et al, 1988). Most models of the LH surge use both estradiol and progesterone priming because ovariectomized rats treated with only estradiol show a physiological, but blunted LH surge, but treatment with progesterone increases the magnitude and duration of the surge (DePaolo and Barraclough, 1979).…”

Steroid signaling in mature follicles is important for Drosophila ovulation

“…This process consists of a complex series of events tightly coordinated by a network of paracrine and endocrine signals, most notably in mammals by steroid progesterone signaling, in mature follicles (3)(4)(5). Pharmacological inhibition of progesterone synthesis or genetic disruption of the progesterone receptor results in an ovulation failure due to a lack of follicle wall proteolysis or follicle rupture (6,7). The signaling mechanism by which progesterone regulates a spatiotemporal proteolysis leading to a successful follicle rupture is largely unknown.…”

Reversible infertility in a liver receptor homologue-1 (LRH-1)-knockdown mouse model

“…In rodents, ovulation is preceded by a small increase in progesterone as well as an increase in oestradiol, prolactin and LH. The preovulatory rise in progesterone has been shown to be mandatory for ovulation (Hibbert et al 1996;Robker et al 2000) and its absence in LRH-1-KD mice could largely explain the observed infertility phenotype. The progesterone receptorknockout (PRKO) mice, in which both progesterone receptors have been inactivated, are completely infertile (Robker et al 2000;Conneely et al 2003), like LRH-1-KD mice.…”