ARTICLE ON PROGESTERONE AND ITS SYMPTOMS

BY SUNNDEEP CHOPRA:

Progesterone (is a C-21 steroid hormone normally involved in the female menstrual cycle, pregnancy)  is normally secreted or thrown up by the luteinized theca-granulosa cells of the  corpus luteum. A minute or negligible amount is however secreted by/from the theca-granulosa cells of the follicle and also from the ovarian stroma (a peculiar soft tissue, abundantly supplied with blood vessels).

Progesterone is inextricably bound to or closely linked with albumin (79%) and corticosteroid binding globulin (17.7%). The same is metabolised  or then manifested in the liver and excreted or ejected as sodium pregnanediol glucuronide (pregnanediol) in the urine. This metabolite has little or no progestational activity.  

Only 20% of secreted progesterone is conjugated ( separated or then segregated before combining to form a compound) and appears in the urine. The fate of the remaining 80% is unclear and the subject of intense speculation.

17-alpha-hydroxy progesterone is an important/significant byproduct of the ovary. The same is metabolized in the ovary and subsequently reduced to pregnanetriol.

PROGESTERONE LEVELS: The daily production or churning out of progesterone is around 2-3 mg during the follicular (menstrual cycle) phase and in the 20-30 mg vicinity during the luteal (latter phase of the menstrual cycle).

Daily secretion or ejection of pregnaediol in the urine is less than 1 mg in the follicular phase and 3-6 mg in the luteal phase.

The serum value of progesterone is less than 1 ng/mg in the follicular phase and 5-15ng/ml in the mid luteal phase.

Progesterone acts on all the organs of the genital tract or passage and breasts subject to their sensitization by oestrogen.

Ø  Uterus: Progesterone produces or gives rise to myohyperplasia (related to the female uterus) and diminishes or reduces the contractility or flexibility of the myometrium (smooth muscle forming the wall of the uterus). It however increases or enhances the tone of the circular muscle fibres at the isthmus (a narrow connection between two larger bodies or parts). It also rekindles secretory activity in/within the enometrium and consequently enhances secretion of the glands rich in glycogen.

Ø  Vagina: The maturation or development of the vaginal epithelium (one of the four basic types of animal tissue) is hindered or then impeded. There is accelerated shedding of the intermediate cells with folded edges and a proclivity towards clumping or bunching.

Ø  Fallopian Tubes: The epithelial cells are stimulated or then energized into secreting clear mucus that facilitates the migration of the ovum. Tubular mobility is however decreased/slowed down or diminished and may cause tubal pregnancy.

Ø  Breasts: It produces hypertrophy and stimulates growth of the acinar structures along with oestrogen .

Ø  General: Progesterone is thermogenic or heat causing and Inherently capable of rising the body’s temperature by 0.2 to 0.5 degrees Celsius. There may be enhanced deposition or depositing of fat in the tissues. The same relaxes or then promotes a feeling/sense of well being during pregnancy. It promotes or stimulates the secretion of sebum by the skin and also causes or then is responsible for fluid retention like in the case of other steroids.

THE PRINCIPAL or solitary/most significant negative feedback action of progesterone is upon/on the midcycle gonadotrophin surge and it is also wholly responsible for it’s aborted duration.

Left to it’s own devices, progesterone does not appear to be capable of exerting a positive feedback effect. However, its rise or upsurge during the preovulatory period is directly linked to or intricately related with the FSH surge caused by its positive feedback action.

Progesterone initially stimulates or facilitates the production of GnRH at the lower level and conversely inhibits or impedes the same at the higher lebvel.

Progesterone acts or then is active through both intraovarian and central negative feedback mechanisms and devices to suppress and inhibit new follicular growth.

CONTRACEPTION: Combined preparations or amalgams or then complex compounds of both oestrogen and progestogen are widely or predominantly used as contraceptive or birth control pills. Progestogens are used as contraceptives in the following forms:

·         Minipill (oral)

·         Levonorgestrel: emergency contraceptive

·         Depomedroxyprogesterone acetate (DMPA); injectable

·         Norethisterone enanthate: NET-EN (injectable)

TYPES OR CLASSIFICATION:

Progesterones are normally divided or classified with respect to their derivatives and contents;

I Progesterone-natural Progesterone

II. Pregnane progestogens (do not alter or change carbohydrate metabolism)-17 alpha hydroxy progesterone caproate, medroxyprogesterone acetate, chlormanidone acetate, Cyproterone acetate.

III. Norpregnane progestogens- nomegesterol acetate, gestonorone caproate

IV. Stereoisomer of progesterone: retroprogesterone (they do not inhibit ovulation)- dydrogesterone

V. 19 noprogesterone derivatives: (nopregnanes)- demegestone, promegestone, nestorone, trimegestone

VI. Alkyl derivatives of 19 nortestosterone:

A.      Oestrane Steroids: they alter carbohydrate metabolism slightly. Metabolically they are converted into norethisterone- norethisterone, norethisterone acetate, norethynodrel, ethynodiol diacetate, lynestreno

B.      Gonane Steroids: they have excellent contraceptive efficacy and cycle control. Lesser side effects. They are more potent and efficacious when compared to oestrane steroids-----norgestrel, levonorgestrel, desogestrel, etonogestrel, gestodine, norgestimate, norelgestromin, dienogest.

VII. Spironolactone derivatives: drospirenone

VIII. Unsaturated 19 norsteroid---gestrinone.

SYMPTOMS AND TREATMENT OF THE SYMPTOMS:

Ø  Dysfunctional Uterine Bleeding (DUB): Progestogen administration or initiation is inherently capable of causing secretory or then absorption related changes in the endometrium. Thus, the same is prone to be more then active in cases of anovulatory rather than ovulatory DUB. This therapy is ideal or really beneficial in the onset of puberty, adolescents or adolescence and pre-menopausal period.

Norethisterone or then norethisterone acetate 5 mg thrice daily is extremely potent in both inhibiting as well as gradually stopping the flow of blood (bleeding). The same preparation is either used from day 5 to 25 or then from day 15 to 25 of the cycle in order to regulate and regimen the same.

Mode of Action: Progesterone decreases or reduces synthesis of oestrogen receptors in the endometrium:

·         It converts oestradiol to less potent oestrone through requisite enzymatic action

·         It inhibits or hinders mitotic activity of the endometrial cells.

·         It induces the enzyme oestradiol dehydrogenase- which in turn degrades or reduces oestradiol in the endometrium.

·         Progesterone mostly acts as an antioestrogen on the endometrium.

Endometriosis: The usage or then use of progestogens induces or gives rise to a hyperprogestogenic hypoestrogenic state. progestogens cause or then begin decidualisation  (postovulatory process of endometrial remodeling in preparation for pregnancy) of endometrial tissue. Atrophy (partial or then complete wasting away of a part of the body) of the glands, fibrosis and atrophy of the ectopic endometrial tissues are a direct consequence of the same.

The commonly used drugs to alleviate or improve this condition are medroxyprogesterone acetate or dydrogesterone or then derivatives of 19-norethisterone.

Dose: Norethisterone 5 mg or medroxyprogesterone 10 mg either twice or thrice daily for a continuous period of 6-9 months. The patient remains amenorrhoeic (related to the suppression of normal menstrual flow for any reason other than pregnancy).

Intramuscular injections of medroxyprogesterone actetate 100 mg every two weeks for 4 doses and then 200 mg every month for 4 doses will produce or induce amenorrhea and the same are especially suitable in older women who have duly completed the family cycle.

Primary dysmenorrhea: Dydrogesterone 5 mg starting from day 5 onwards for 20 days relieves or improves dysmenorrheal by most probably inhibiting or reducing uterine contractions while sparing the consequent ovulation.

Luteal Phase Defect (LPD): A daily intramuscular injection of 125 mg of progesterone in oil, beginning on the day after the BBT (basal body temperature or then the lowest body temperature attained by the human body in a state of rest) shift until menstruation occurs or then if conception has taken place until/after 10-12 weeks of/after gestation in a proven case.

Endometrial Hyperplasia and endometrial carcinoma: Its role or then efficacy in the treatment of an endometrial carcinoma is co-dependent upon the number of steroid receptors present on the tumour. A well differentiated or then isolated grade I endometrial carcinoma is thought to have the highest number of receptors. Such cases are extremely conducive towards the initiation of progestogen therapy. Recurrent or repetitious endometrial carcinoma with a good or favourable steroid receptor status is also amenable to this form of treatment.

Dose: 17 alpha hydroxyprogesterone caproate 1000 mg intra muscular daily for 1 week, thereafter once a week for the next 3 months and then fortnightly for the next 1 year. Alternatively, medroxyprogesterone acetate 400 mg intra muscular once a week for 3 months and subsequently on a fortnightly basis for the next 1 year.

Premenstrual syndrome: Progestogens have been tried or induced to relieve the resultant symptoms on the basis of the hypothesis that progesterone deficiency or shortage may be the causal factor. Dydrogesterone 5 mg twice daily from day 5 onwards for the next 20 days in each cycle for 3-6 cycles may be tried.

Luteal Support: It is usually given or administered on the day after oocyte retrieval for ART (product or process of deliberately arranging items) . Progesterone use is indicated in any of these forms.

·         Progesterone in oil 50 mg daily

·         Vaginal suppository 200 mg twice daily or

·         Micronized progesterone orally 200 mg twice daily.

The ingestion of these drugs is normally for a 14 day or two week period.

Postponement of menstruation: Norethisterone preparation 5 mg tablet thrice daily should be started at least three days prior to the onset of menstruation in order to postpone or push back the onset of the menstrual period or cycle and the same practice should be continued until the patient desires to have her menstrual cycle or period. The period normally manifests itself 48-72 hours after the cessation of this mode of treatment. Caution: This form of treatment should not be resorted to casually as it has the inherent potential to irrevocably disturb or disrupt the menstrual pattern.

Hormone Replacement Therapy (HRT): Progestins and oestrogen make unlikely bedfellows in an unusual combination as a hormone replacement therapy in cases of women whose uterus is still alive and kicking as this prevents or inhibits the onset of endometrial hyperplasia. Progestins can be used cyclically for the last 12-14 days of the cycle or then continuously in conjunction with oestrogen.

Combined Preparations (oestrogen and progestogen):

Diagnostic: The combined preparations may be used or then made use of as an oestrogen-progesterone challenge test in amenorrhea (the absence of a menstrual period in a woman of reproductive age) in order to exclude or rule out uterine pathology. The conspicuous absence of resultant bleeding signifies or then points toward the presence of uterine synechae.

Therapeutic:

·         Contraception: The commonest and most widely prevalent use of combined preparations is in the field of fertility control.

·         Dysfunctional uterine bleeding

·         Endometriosis

·         Dysmenorrhea

·         Postponement of period

·         Premenstrual syndrome

·         Idiopathic Hirsutism: cyclic therapy of combined preparations containing 50 mg |ug of ethinyl oestradiol together with new progestin is far more effective or efficacious.

·         Hormone replacement therapy (HRT)

SIDE EFFECTS OF PROGESTOGEN:

·         Nausea- subsides gradually

·         Leg cramps

·         Mastalgia (breast pain)

·         Weight gain on account of salt and water retention

·         Acne- due to androgenic progestins

·         Scanty periods- due to above reason

·         Loss of libido- due to androgenic progestins

·         Virilism-on account of the above mentioned reason

·         Headaches-with the notable exception of migraines

·         Depression and mood changes- can be directly attributed to low levels of pyridoxine as progestins alter or change the tryptophan metabolism

·         Lipid profile- increase in LDL (cholesterol level)  and decrease in HDL (cholesterol level) level.