Melatonin effects on ovarian follicular cells: a systematic review

SUMMARY Melatonin is known for its effects on both the sleep and reproductive system of mammals. The latter has melatonin receptors type 1 and 2, which act to regulate, among other things, cyclic AMP. Notwithstanding all the literature data, there is still no sound knowledge or a clear understanding of the hormone's action on the physiology of ovarian follicular cells. OBJECTIVE To review and evaluate studies about melatonin action on the ovarian granulosa/theca interna cells from the literature. METHODS The systematic review was carried out according to the PRISMA recommendations. The MEDLINE and Cochrane primary databases were consulted with the use of specific terms. There was no limitation on language or publication year. RESULTS Seven papers about melatonin action on granulosa cells were selected. The following can be attributed to the hormone's effects: a) progesterone increase in culture medium; b) increased estrogen production; c) antagonistic action on estrogen; d) improvement in cell quality resulting in improved embryo and higher pregnancy rates; e) improved cell proliferation via MAPK; f) reduction of free radicals. Nevertheless, there are contrarian papers reporting a reduction in progesterone production. CONCLUSION Melatonin interferes in sex steroid production, boosting progesterone output. Such action may help improve oocyte quality.

RESUMO A melatonina é conhecida por seus efeitos no sono e no sistema reprodutivo dos mamíferos. Este último tem receptores de melatonina tipos 1 e 2, que atuam para regular, entre outras coisas, o AMP cíclico. Apesar de todos os dados da literatura, ainda não há um conhecimento sólido ou uma compreensão clara da ação do hormônio na fisiologia das células foliculares ovarianas. OBJETIVO Revisar e avaliar estudos da ação da melatonina na literatura sobre as células internas da granulosa/teca ovariana. MÉTODOS A revisão sistemática foi realizada de acordo com as recomendações do Prisma. As bases de dados primárias Medline e Cochrane foram consultadas com o uso de termos específicos. Não houve bar na língua ou ano de publicação. RESULTADOS Sete artigos sobre a ação da melatonina nas células da granulosa foram selecionados. O que se segue pode ser atribuído aos efeitos do hormônio: a) aumento de progesterona no meio de cultura; b) aumento da produção de estrogênio; c) ação antagônica no estrogênio; d) melhoria na qualidade celular, resultando em melhor embrião e maiores taxas de gravidez; e) melhor proliferação celular via MAPK; f) redução de radicais livres. No entanto, existem artigos controversos relatando redução na produção de progesterona. CONCLUSÃO A melatonina interfere na produção de esteroides sexuais, aumentando a produção de progesterona. Tal ação pode ajudar a melhorar a qualidade do oócito.

Effect of the human follicle-stimulating hormone-binding inhibitor and its N-terminal fragment on follicle-stimulating hormone-induced progesterone secretion by granulosa cells in vitro.

Intrafollicular factors play an important role in folliculogenesis. The follicle-stimulating hormone (FSH)-binding inhibitor (FSHBI), purified by our laboratory from human ovarian follicular fluid, has been shown to suppress ovulation and induce follicular atresia/apoptosis in mice as well as impair fertility in marmosets, the New World monkeys. The octapeptide, a peptide corresponding to the N-terminal region of human FSHBI (hFSHBI), has been synthesized and also shows FSHBI activity in vitro. In the present study, we have attempted to identify the mechanism of action of the peptide in granulosa cell cultures. Rat granulosa cell cultures were treated with varying concentrations of the octapeptide or partially purified hFSHBI (gel chromatography fraction hGF 2) in the presence or absence of human FSH (hFSH) and the amount of progesterone (P;4) secreted in the culture supernatants after 3 h/48 h was estimated. Both hGF2 and the octapeptide failed to alter basal levels as well as 8-bromo cAMP-induced P;4 production, while FSH-induced P 4 secretion was inhibited in a dose-dependent manner. These studies reveal that the octapeptide, a fragment of FSHBI, and the native protein have similar activity in vitro and both compounds alter FSH action at the receptor level upstream of cAMP formation.

Novas perspectivas no tratamento da endometriose pélvica / Perspectives for the treatment of endometriosis: a new approach

A endometriose pélvica é uma doença freqüente nos serviços especializados em dor pélvica e infertilidade. Os tratamentos existentes atualmente baseiam-se na indução de amenorréia, seja por atrofia endometrial ou por decidualização. Não há um consenso em relação ao tratamento de pacientes com dor pélvica ou infertilidade. A busca de novos tratamentos é contínua e alguns estudos já apontam para novas direções, como imunomoduladores, agentes antiinflamatórios e substâncias de ação hormonal diferenciada. A investigação da fisiopatologia da endometriose, especialmente a influência de processos inflamatórios, do estresse oxidativo local e de agentes angiogênicos, levará a terapias direcionadas às fases iniciais da doença, com resultados definitivos. Os autores apresentam uma revisão da literatura existente e avaliam as novas perspectivas para o tratamento de pacientes com endometriose.

Progesterone potentiating effect of Dipsacus mitis D. Don for its contraceptive action in hamster.

A pure compound, isolated from ethyl acetate extract (root) of D. mitis D. Don, prevented pregnancy by 100% in adult female hamster but partially in rat when administered orally on Days 1-7 and 1-10 post-coitum respectively. The effective dose in both species was 150 mg/kg. Using uterine wet weight in ovariectomized immature rat as bioassay method, the compound was found to be devoid of estrogenic and antiestrogenic property. On examination for progestational and antiprogestational activity, using trauma-induced deciduoma formation in immature rat uterus as end points, the compound (per se) did not show the former activity but in a conjoint treatment with progesterone it augmented the action of latter. The compound was assumed to act by potentiating progesterone biosynthesis, the excess of which might be the cause for interruption of pregnancy in hamster. This is the first study to report contraceptive efficacy and mode of its action at the uterine level.

Hormonal requirement for blastocyst implantation and a new approach for anti-implantation strategy.

There is a growing awareness of a need for developing novel methods of contraceptive technology which should not only be effective in providing protection against conception but also take into consideration the reproductive health issues confronting men and women. This paper considers the process of embryo implantation as one such potential target. The hormonal basis of embryo implantation in primates has been discussed to indicate that progesterone, and not estrogen, from ovarian source is the primary determinant of embryo-endometrial maturation and their synchronization for implantation. Thus, low dose administration of the anti-progesterone, mifepristone, during early luteal phase has been shown to be an effective anti-implantation approach to for fertility control. Furthermore, the dissociation of endometrial-hormonal synchrony at the time of blastocyst implantation following the post-ovulatory mifepristone administration has been shown to be the physiological basis of its anti-implantation effect with undisturbed circulatory hormone profiles and ovarian functions. Further studies are required to appreciate the full potential and to mollify the limitations of this approach.

Producción de anticuerpos antiprogesterona apartir de la yema de huevo de gallinas y del suero sanguíneo de conejos, para ser utilizados en radioinmunoanálisis / Production of antibodies against progesterone from the eggyolk of hens and from rabbit blood serum to be used in radioimmunoassay

Se indujo la producción de anticuerpos contra progesterona en gallinas Leghorn y conejos Nueva Zelanda, con el propósito de utilizarlos para establecer un Radioinmunoanálisis (RIA) para determinar progesterona. La extracción de anticuerpos de la yema de huevo de las gallinas inmunizadas se realizó con 2-propanolyacetona. Los anticuerpos del suero sanguíneo de conejo se extrajeron con solución de sulfato de amomio. Los anticuerpos de la yema del huevo mostraron elevada afinidad y especificidad hacia la progesterona. La sensibilidad del RIA establecido con estos anticuerpos fue de 0.27 ng/ml; los coeficientes de variabilidad intraensayo e intraensayo fueron de 19.6 y 22.2 por ciento, respectivamente. Hubo una correlación de 0.94 entre los valores de progesterona determinados con un estuche comercial y los establecidos con los anticuerpos de la yema. Los anticuerpos obtenidos del suero de conejo también tuvieron elevada afinidad y especificidad hacia la progesterona. La sensibilidad de RIA que utilizó este anticuerpo fue de 0.23 ng/ml, el coeficiente de variabilidad intraensayo de 14.7 por ciento y el interensayo de 22.7 por ciento. Los valores progesterona medidos con un estuche comercial y con el RIA establecido con los anticuerpos del conejo tuvieron una correlación de 0.96. Se concluye que la yema de huevo de gallinas inmunizadas es una fuente práctica de anticuerpos antiprogesterona de calidad comparable a la de los anticuerpos obtenidos a partir de suero sanguíneo de conejos. La producción de anticuerpos antiprogesterona extraídos de la yema del huevo de gallinas inmunizadas, fue 2.5 vecesa mayor que la obtenida del suero sanguíneo de conejos inmunizados contra el mismo antígeno