Posted by SalArmy4me on August 29, 2001, at 18:03:13
In reply to Progesterone for PMS/PMDD, posted by Ariella on August 29, 2001, at 12:35:46
Epperson, C. Neill MD. Wisner, Katherine L. MD. Yamamoto, Bryan PhD. Gonadal Steroids in the Treatment of Mood Disorders. Psychosomatic Medicine. 61(5):676, September/October 1999:
"Progesterone
Premenstrual Syndrome.
Since the 1950s, when Katharina Dalton (151, 152) championed the use of progesterone in the treatment of PMS, seven double-blind, placebo-controlled studies have resoundingly failed to prove its efficacy (23, 153–158). Only three studies (159–161) have found any beneficial effect of progesterone above that of placebo. Table 3 describes the findings of Dalton’s early open-label reports and those of the 11 double-blind, placebo-controlled studies of progesterone in the treatment of PMS. Although the subjects included in the controlled studies were all prospectively screened over (in most cases) two menstrual cycles to confirm the PMS diagnosis, there are significant methodological differences among the studies that make them difficult to interpret as a group. All investigators claimed to exclude women with comorbid psychiatric disorders, which is necessary in the diagnosis of PMS; however, only Freeman et al. (23, 153) did so using structured clinical interviews, whereas five relied on unstructured clinical interviews (155, 156, 158–160) and three (154, 157, 161) did not describe the method used to exclude these women. A large percentage of women in three studies (23, 153, 158) reported a history of psychiatric illness, usually major depression. Each of these studies found progesterone to significantly reduce PMS symptoms, but not above those reductions achieved with placebo. Measurements used to assess both physical and psychological symptoms varied greatly, with some using validated daily rating instruments, such as the MDQ (162) and the Daily Symptom Report (163), and others using nonvalidated scales. These factors are important, because the degree to which women included in the studies meet criteria for PMDD as well as PMS depends on the number of mood symptoms that significantly interfere with a woman’s functioning during the luteal phase. Moreover, both diagnoses of PMDD and PMS depend on the absence of comorbid psychiatric disorders. Route of administration and dosage of progesterone used varied as well. However, Freeman et al. (153) found no difference between placebo and progesterone despite using doses as high as 800 mg/d.Two relatively recent studies (160, 161) found progesterone to be significantly better than placebo in decreasing a limited number of mood and physical symptoms, and one (159) reported significant differences with respect to depressed mood, subjective sense of loss of control, water retention, and swelling, as measured by daily ratings, and in anxiety, as measured by the Spielberger Anxiety Scale. Baker et al. (160) carefully excluded women with past or present psychiatric disorders and randomly assigned 34 women to receive either placebo or progesterone vaginal suppositories (200 mg twice a day during the luteal phase) for 7 months. Progesterone was found to be significantly more effective than placebo on ratings pertaining to feelings of guilt and low self-image as well as nervous symptoms (anxiety, tension, mood swings, irritability, and lack of control). However, between-group differences with respect to overall scores on the clinician-rated scales (Spielberger self-evaluation rating, the Profile of Mood States, BDI, and Hamilton Anxiety Rating Scale) were lacking. Using vaginal progesterone 400 mg BID during the luteal phase, Magill (161) showed that progesterone was significantly more effective in reducing some of the physical and psychological symptoms that the women in this sample found most problematic. Women with prospectively diagnosed PMS received progesterone (N = 50) or placebo (N = 43). The “most problematic symptoms” that were most frequently reported were bloating, depression, irritability, tension, and tiredness. Vanselow et al. (158) found no difference between oral micronized progesterone and placebo with respect to mood symptoms in PMS subjects with a “high level” of personal and family history of major depression. In addition, they noted a negative correlation between plasma allopregnanolone levels and anxiety, which suggests the neurosteroid may play a role in the pathophysiology of anxiety associated with PMS. Each of these studies can be criticized for not using structured clinical interviews to determine past and present psychiatric history. Past history of major depression may be a factor in treatment outcome because there is evidence that GABAergic function may be different in women with PMS who have experienced major depression and those who have not (104). Considering the seven studies with negative findings, progesterone is not considered an effective treatment for PMS.
Postpartum Depression.
Unlike the flurry of investigation regarding the potential efficacy of progesterone in the treatment of PMS, there has been only one report of progesterone in the treatment of postnatal depression. Dalton (164) investigated the use of progesterone in the prophylaxis of recurrent PPD by conducting a naturalistic study of 181 women who had suffered “idiopathic postnatal depression,” defined as “the first psychiatric illness, severe enough to require medical help, occurring within 6 months of childbirth.” The clinical status of women who requested information regarding progesterone prophylaxis was followed by mail. The 181 women who were treated with prophylactic progesterone for 2 months or until the return of menstruation had a recurrence rate of 7%, compared with a rate of 67% in the 21 women who did not receive progesterone treatment. According to Dalton, women suffered no adverse effects of postpartum progesterone administration, and breast-feeding was enhanced. These findings have not been confirmed by other open-label or controlled studies.Does Exogenous Administration of Gonadal Steroids Cause Depression?.
Ten to forty percent of OCP users develop mild to moderate depressive “syndromes,” with those who have had a previous depressive episode most at risk for this adverse side effect (165). According to clinical lore, progesterone is the offending agent when women become depressed and/or irritable while taking OCPs. However, one double-blind, placebo-controlled study demonstrated that, compared with placebo, 14% and 18% more women experienced mild depressive symptoms on a progestogen-dominated OCP and estrogen-dominated OCP, respectively (p = .05). Another study found that addition of medroxyprogesterone acetate 10 mg/d for 14 days to cyclic transdermal estrogen treatment produced no consistent adverse physical or psychological effects compared with placebo independent of a history of PMS (166). In a randomized, placebo-controlled study, Graham et al. (167) found that women from two centers (Edinburgh, Scotland, and Manila, Philippines) who were randomly assigned to receive a combined oral contraceptive reported more adverse affects on mood, whereas those receiving a progestogen-only pill reported some improvement in well-being. Although these finding do not implicate progesterone as the offending agent, there is a recent case report of two women who developed severe psychiatric disorders secondary to the use of Norplant (levonorgestrel). Each patient had onset of depressive symptoms with panic attacks within 2 months of Norplant insertion. Both met DSM-III-R criteria for major depression and panic disorder at the time of presentation. Neither had any previous psychiatric or substance abuse history, and both had complete resolution of symptoms within 1 month of Norplant removal. Additional evidence of the potential of progesterone to adversely affect mood comes from a study of 22 postmenopausal women who were given either estrogen for 21 days with a subsequent break of 7 days or estrogen throughout the cycle with progestogen given the last 11 days of the cycle. The women who were cycled with progestogen experienced substantial cyclicity in both mood and physical symptoms, with negative mood changes starting 1 to 3 days after progestogen was added (168). These findings were later confirmed by the same group (169) and are consistent with those of others (120, 170) but not with those of Kirkham et al. (166)."------------------------------------------------
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